Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same

ABSTRACT

Compounds having the formula (I),  
                 
 
     G is a novel side chain selected from C 2-6 alkenyl, A 3 -aryl, —OR 18 , heteroaryl, A 1 -cyano, A 2 —OR 17 , A 1 —C(═O)R 18 , A 1 —CO 2 R 18 , A 1 —C(═O)NR 18 R 19 , A 1 —OC(═O)R 18 , A 1 —NR 18 C(═O)R 19 , A 1 —OC(═O)NR 18 R 19 , A 1 —NR 18 CO 2 R 19 , A 1 —NR 18 SO 2 R 17 , A 1 —SO 2 R 17 , A 1 —NR 20 C(═O)NR 18 R 19 , and A 1 —SR 18 ; or when y is 0 or when W is not NHR 22 , G may be A 1 -heterocyclo, wherein Al is a bond, C 1-6 alkylene or C 2 -alkenylene, A 2  is C 1-6 alkylene or C 2-6 alkenylene, and A 3  is C 2-6 alkenylene; W is selected from —NR 21 R 22 , —OR 23 , —NR 21 C(═O)R 24 , —NR 21 CO 2 R 24 , amidino, guanidino, or a heteroaryl, heterocyclo or C 3-7 cycloalkyl as defined in the specification, and X and R 1  through R 24  are as defined in the specification, are effective as modulators of melanocortin-receptors, particularly MC-1R and MC-4R.

RELATED INVENTION

[0001] This application claims the benefit of U.S. pat. applicationsSer. Nos. 60/273,206, and 60/273,291, filed Mar. 2, 2001, the entirecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds useful in treatingdiseases responsive to modulation of melanocortin receptors, to methodsof treating such diseases, and to pharmaceutical compositions comprisingsame.

BACKGROUND OF THE INVENTION

[0003] Melanocortin peptides, particularly α-melanocyte stimulatinghormone ((α-MSH), have a wide range of effects on biological functionsincluding feeding behavior, pigmentation, and exocrine function. SeeWikberg et al., “New Aspects on the Melanocortins and their Receptors,”Pharmacological Research, Vol. 42, No. 5 (2000), at pp. 393-420. Thebiological effects of α-MSH are mediated by a sub-family of Gprotein-coupled receptors, termed melanocortin receptors. See Wikberg etal., supra. There are four melanocortin receptors: MC-1R, MC-3R, MC-4R,and MC-5R (MC-2R is not a receptor for α-MSH but is theadrenocorticotropic hormone {ACTH} receptor). Activating any one ofthese receptors results in stimulation of cAMP formation.

[0004] MC-1R was first found in melanocytes. Naturally occurringinactive variants of MC-1R in animals were shown to lead to alterationsin pigmentation and a subsequent lighter coat color. From these andother studies, it is evident that MC-1R is an important regulator ofmelanin production and coat color in animals (or skin color in humans).MC-3R is expressed in the brain and peripheral tissues, and knock-outstudies have revealed that MC-3R is responsible for alterations infeeding behavior and body weight. MC-4R is primarily expressed in thebrain. Genetic knock-outs and pharmacologic manipulation of MC-4R inanimals have shown that agonizing MC-4R causes weight loss andantagonizing MC-4R produces weight gain. MC-5R is ubiquitously expressedin many peripheral tissues and in the brain, but its expression isgreatest in exocrine glands. Genetic knock-out of this receptor in miceresults in altered regulation of exocrine gland function, leading tochanges in water repulsion and thermoregulation.

[0005] Much attention has been focused on the study of MC-3R and MC-4Rmodulators and their use in treating body weight disorders, such asobesity and anorexia. For example, WO 00/74679 to Merck & Co.,Inc.,“Substituted Piperidines as Melanocortin-4-Receptor Agonists,”(Dec. 14, 2000), and WO 99/64002 also to Merck & Co Inc.,“Spiropiperidine Derivatives as Melanocortin Receptor Agonists,” (Dec.16, 1999), disclose compounds that reportedly are selective agonists ofMC-4R. Each of the compounds of WO 00/74679 and WO 99/64002 has abicyclic terminal group, typically tetrahydroisoquinoline. Isoquinolinecompounds, more particularly tetrahydro-isoquinoline-based compounds,useful as melanocortin (MC) receptor agonists and antagonists aredisclosed in U.S. Pat. No. 6,127,381, “Isoquinoline CompoundMelanocortin Receptor Ligands and Method of Using Same,” issued Oct. 3,2000 to Basu et al. See also WO 01/91752, WO 01/70708, and WO 01/70337to Merck and WO 02/00654 to Pfizer Products Inc., reportedly disclosingcompounds for use as MC-4R agonists. Individual compounds can bind tomultiple MC receptors, with different levels of affinity. Yet it isadvantageous in treating diseases for compounds to be selective for oneor more particular MC receptors. See, e.g., WO 00/58361 to Proctor &Gamble Co., “Melanocortin Receptor Ligands” (disclosing compounds thatreportedly are selective for MC3R and MC4R in preference to MC-1R); andWO 99/54358 to Quadrant Holdings Cambridge Ltd., “Melanocortin ReceptorLigands” (disclosing compounds that reportedly are selective for MC3R,MC4R and/or MC5R).

[0006] The melanocortin peptides have potent physiological effectsbesides their role in regulating pigmentation, feeding behavior, andexocrine function. In particular, α-MSH has been shown to induce apotent anti-inflammatory effect in both acute and chronic models ofinflammatory diseases including inflammatory bowel disease, renalischemia/reperfusion injury, and endotoxin-induced hepatitis. SeeCatania et al., “α-MSH in Normal Human Physiology and Disease States,”Trends in Endocrinology and Metabolism, Vol. 11, No. 8 (2000) at pp.304-308. Administration of α-MSH (either i.p. or i.v.) in these modelsresults in substantial lessening of inflammation-mediated tissue damage,a significant decrease in leukocyte infiltration, and a dramaticreduction in elevated levels of cytokines (e.g., TNF-α), chemokines(e.g., MCP-1, IL-8), and inflammatory mediators (e.g., i-NOS andICAM-1), to near baseline levels. Earlier studies had shown that α-MSHacts as an “anti-cytokine” in many acute inflammatory models, in effectantagonizing the pro-inflammatory actions of TNF-α, IL-1β, and IL-6.

[0007] The anti-inflammatory actions of α-MSH are mediated by MC-1R.MC-1R is expressed in cells that are important regulators of the immuneresponse: monocyte/macrophages, neutrophils, endothelial, and mastcells. See Catania et al., cited above. Stimulation with α-MSH resultsin a dampening of the inflammatory response in these cells, includinginhibition of nitric oxide formation, decreased expression ofco-stimulatory molecules and adhesion receptors, and importantly, anincrease in the expression of IL-10; a cytokine with potentanti-inflammatory actions. Studies have shown that MC-1R selectivepeptides are as efficacious as α-MSH in eliciting an anti-inflammatoryresponse. See Wikberg, “Melanocortin Receptors: Perspectives for NovelDrugs,” European Journal of Pharmacology, Vol. 375 (1999), at pp.295-310, and WO 99/57148 to WA Pharma AB (1999), “Melanocortin 1Receptor Selective Compounds.”

[0008] The mechanism by which agonism of MC-1R results in ananti-inflammatory response is likely through inhibition of thepro-inflammatory transcription activator, NF-κB. NF-κB is a pivotalcomponent of the pro-inflammatory cascade, and its activation is acentral event in initiating many inflammatory diseases. In a typicalinflammatory response, NF-κB is activated in response to an inflammatorystimulus and once activated, induces expression of a wide array ofpro-inflammatory genes. See Tak and Firestein, “NF-κB: a Key Role inInflammatory Diseases,” The Journal of Clinical Investigation, Vol. 107(2001), pp. 7-11. Activation of MC-1R, and subsequent generation of cAMPand/or decreased production of nitric oxide, has been shown to inhibitactivation of NF-κB. See Manna and Aggarwal, “α-MSH Inhibits the NuclearTranscription factor NF-κB Activation Induced by Various InflammatoryAgents,” The Journal of Immunology, Vol. 161 (1998), pp. 2873-2880.Thus, α-MSH exerts anti-inflammatory actions through stimulation ofMC-1R on cells involved in the inflammatory response and subsequentinhibition of the activation of the pro-inflammatory transcriptionfactor NF-κB. Additionally, studies show that anti-inflammatory actionsof α-MSH may be, in part, mediated by agonism of MC-3R and/or MC-5R. SeeWO 00/05263 to William Harvey Research Limited (2000), “Compounds forUse in the Treatment of Inflammation.”

[0009] The present invention provides compounds useful as modulators ofthe melanocortin receptors, including selective modulators of MC-1Rand/or MC-4R. Compounds that reportedly are selective agonists of MC-1Rare disclosed in WO 99/57148, cited above, and selective antagonists ofMC-1R are disclosed in WO 99/43709 to The Regents of the Univ. ofCalif., “Melanocortin Receptor Antagonists and Modulations ofMelanocortin Receptor Activity.” Both WO 99/57148 and WO 99/43709disclose large polypeptides. Small molecule inhibitors are advantageousin comparison to large polypeptides as they are less likely to induceimmune reactions in patients and are more amendable to oral delivery.There remains a need for a small molecule useful as an MC-1R agonist,which is provided by the present invention. Melanocortin receptor,modulators are also disclosed in U.S. patent application Ser. No.______, filed concomitantly herewith by the same inventors herein andassigned to the present assignee, claiming priority to U.S. patentapplications Ser. Nos. 60/273,206, and 60/273,291, filed Mar. 2, 2001,the entire contents of which is incorporated herein by reference. Alsoincorporated herein is WO 99/58501 to Novo Nordisk.

SUMMARY OF THE INVENTION

[0010] The present invention is directed to compounds having the formula(I), useful as modulators of one or more melanocortin receptors,

[0011] and pharmaceutically-acceptable salts, hydrates, or prodrugsthereof, in which:

[0012] X is N or CH;

[0013] R₁ is hydrogen or C₁₋₆alkyl or is taken together with R₂ or R₃ toform a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl orheterocycle;

[0014] R₂ is hydrogen, aryl, cycloalkyl, heteroaryl, or heterocyclo; orC₁₋₆alkyl or C₂₋₆alkenyl optionally substituted with one to three ofhydroxy, alkoxy, halogen, cyano, trifluoromethyl, nitro, amino,alkylamino, aryl, cycloalkyl, heteroaryl, and/or heterocyclo; or R₂ istaken together with R₁ or R₃ to form a monocyclic or bicyclic aryl,cycloalkyl, heteroaryl or heterocycle;

[0015] R₃ is hydrogen or C₁₋₆alkyl or is taken together with R₂ to forma monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle;

[0016] E is E₁, E₂, E₃ or E₄, wherein

[0017] E₄ is —NR₁₁R₁₂;

[0018] G is selected from C₂₋₆alkenyl, A₃-aryl, —OR₁₈, heteroaryl,A₁-cyano, A₂—OR₁₇,

[0019] A₁—C(═O)R₁₈, A₁—CO₂R₁₈, A₁—C(═O)NR₁₈R₁₉, A₁—OC(═O)R₁₈,

[0020] A₁—NR₁₈C(═O)R₁₉, A₁—OC(═O)NR₁₈R₁₉, A₁—NR₁₈CO₂R₁₉, A₁—NR₁₈SO₂R₁₇,

[0021] A₁—SO₂R₁₇, A₁—NR₂₀C(═O)NR₁₈R₁₉, and A₁—SR₁₈; or when y is 0, orwhen W is a group other than NHR₂₂, G may be A₁-heterocyclo, wherein A₁is a bond, C₁₋₆alkylene or C₂₋₆alkenylene (straight or branched chain),A₂ is C₁₋₆aikylene or C₂₋₆alkenylene, and A₃ is C₂₋₆alkenylene;

[0022] W is selected from —NR₂₁R₂₂, —OR₂₃, —NR₂₁C(═O)R₂₄, —NR₂₁CO₂R₂₄,amidino, guanidino, or a substituted or unsubstituted heterocyclo,heteroaryl, or cycloalkyl selected from azepinyl, azetidinyl,imidazolyl, imidazolidinyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl,1,2-dihydropyridazinyl, pyranyl, tetrahydropyranyl, piperazinyl,homopiperazinyl, pyrrolyl, pyrrolidinyl, piperidinyl, thiazolyl,tetrahydrothiazolyl, thienyl, furyl, tetrahydrofuryl, morpholinyl,isoquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, oxazolyl,tetrahydro-oxazolyl, and C₃₋₇cycloalkyl, wherein said heteroaryl,heterocyclo or cycloalkyl groups may additionally have joined thereto anoptionally substituted five-to-seven membered heterocyclic, heteroaryl,or carbocyclic ring;

[0023] R₄ and R₇ are independently selected from hydrogen, alkyl,substituted alkyl, halogen, hydroxy, alkoxy, and keto;

[0024] R₅, R_(5a), R_(5b), R₆, R_(6a), R_(6b), R₈ and R₉ areindependently hydrogen, halogen, cyano, alkyl, substituted alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, —OR₂₅,—NR₂₅R₂₆, —SR₂₅—S(O)_(p)R₂₆, —C(═O)R₂₅, —OC(═O)R₂₅, —CO₂R₂₅,—C(═O)NR₂₅R₂₆, —NR₂₅C(═O)R₂₆, —OC(═O)NR₂₅R₂₆, —NR₂₅CO₂R₂₆,—NR₂₇C(═O)NR₂₅R₂₆ or —NR₂₅SO₂R₂₆; or R_(5a) and R_(5b), R_(6a) andR_(6b), or R₈ and R₉ taken together form a keto group (═O) or amonocyclic or bicyclic cycloalkyl or helerocyclo joined in a spirofashion to ring E, or alternatively, R_(5a) and/or R_(5b) together withR₈ and/or R₉, or R_(6a) and/or R_(6b) together with R₈ and/or R₉, aretaken to form a fused carbocyclic, heterocyclic, or heteroaryl ring;provided that, when G is a C₁₋₆alkyl substituted with —OR₁₇, —CO₂R₁₈, or—C(═O)NR₁₈R₁₉, then R_(5a), R_(5b), R_(6a), and R_(6b) are hydrogen;

[0025] R₁₀ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl, and hetereocyclo;

[0026] R₁₁ is hydrogen or C₁₋₈alkyl;

[0027] R₁₂ is C₁₋₈alkyl, substituted C₁₋₈alkyl, or cycloalkyl;

[0028] R₁₃, R₁₄, R₁₅ and R₁₆ are selected independently of each otherfrom hydrogen, alkyl, substituted alkyl, amino, alkylamino, hydroxy,alkoxy, aryl, cycloalkyl, heteroaryl, or heterocyclo, or R₁₃ and R₁₄, orR₁₅ and R₁₆, when attached to the same carbon atom, may join to form aspirocycloalkyl ring;

[0029] R₁₇ is alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo,or heteroaryl;

[0030] R₁₈, R₁₉, and R₂₀ are independently selected from hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl,heteroaryl, cycloalkyl, heterocyclo, or C(═O)R₂₈; or when G isNH(C═O)R₁₉, R₁₉ may be a bond joined to W to define a heterocyclo ring;provided, however, that when y is at least one, W is imidazolyl,indolyl, —NR₂₁R₂₂, or —OR₂₃, and G is —NR₁₈C(═O)R₁₉, then R₁₉ is not aC₁-alkyl having the substituent —NR₂₉R₃₁;

[0031] R₂₁ and R₂₂ are selected from hydrogen, alkyl, and substitutedalkyl;

[0032] R₂₃ and R₂₄ are independently hydrogen, alkyl, substituted alkyl,aryl, heteroaryl, heterocyclo, and cycloalkyl;

[0033] R₂₅, R₂₆ and R₂₇ are independently hydrogen, alkyl, substitutedalkyl, cycloalkyl, aryl, heterocyclo, or heteroaryl; or R₂₅ and R₂₆ mayjoin together to form a heterocyclo or heteroaryl, except R₂₆ is nothydrogen when joined to a sulfonyl group as in —S(O)_(p)R₂₆ or—NR₂₅SO₂R₂₆;

[0034] R₂₈ is hydrogen, alkyl, or substituted alkyl;

[0035] R₂₉ and R₃₁, are selected from hydrogen, alkyl, haloalkyl,hydroxyalkyl, phenylalkyl, and alkoxycarbonylalkyl, or R₂₉ and R₃₁ takentogether form a heterocyclo ring;

[0036] n is 0, 1, 2, 3 or 4;

[0037] p is 1, 2, or 3;

[0038] r and s are 0 or 1;

[0039] x is 0, 1, or 2;

[0040] y is 0, 1, 2, 3 or 4; and

[0041] z is 0, 1, or 2.

[0042] The invention is further directed to pharmaceutical compositionscomprising one or more compounds according to formula (I). The inventionis further directed to methods of treating melanocortin-receptorassociated conditions, as defined herein, as well as methods ofagonizing or antagonizing the melanocortin receptors, more particularly,MC-1R and MC-4R. The invention is also directed more generally to smallmolecule inhibitors of MC-1R, and to methods of treating diseasesresponsive to inhibition of MC-1R using a small molecule according tothe invention.

DETAILED DESCRIPTION OF THE INVENTION

[0043] The following are definitions of terms used in thisspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification, individually or as part of another group, unlessotherwise indicated.

[0044] The term “alkyl” refers to straight or branched chain hydrocarbongroups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, aremost preferred. When a subscript is used with reference to an alkyl orother group, the subscript refers to the number of carbon atoms that thegroup may contain.

[0045] The term “substituted alkyl” refers to an alkyl group as definedabove having one, two or three substituents selected from the groupconsisting of halo, amino, cyano, keto (═O), —OR_(a), —SR_(a),NR_(a)R_(b), —(C═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b),—NR_(a)C(═O)R_(b), NR_(a)CO₂R_(b), —OC(═O)R_(a), —OC(═O)NR_(a)R_(b),—NR_(c)C(═O)NR_(a)R_(b), NR_(a)SO₂R_(d), SO₂R_(d), SO₃R_(d), cycloalkyl,aryl, heteroaryl, or heterocycle, wherein the groups R_(a), R_(b), andR_(c) are selected from hydrogen, C₁₋₆alkyl, aryl, heteroaryl,heterocycle, cycloalkyl, or C₁₋₆alkyl substituted with halogen, hydroxy,methoxy, nitro, amino, cyano, —(C═O)H, —CO₂H, —(C═O)alkyl, —CO₂alkyl,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy, acyl, —C(═O)H,-C(═O)phenyl, —CO₂-alkyl, cycloalkyl, —(C═O)NH₂, —(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —C(═O)—(CH₂)₁₋₂NH₂,—C(═O)—(CH₂)₁₋₂NH(alkyl), —C(═O)—(CH₂)₁ ₂N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, phenyl, benzyl, phenylethyl, or phenyloxy. The groupR_(d) may be selected from the same groups as R_(a), R_(b) and R_(c) butis not hydrogen. Alternatively, the groups R_(a) and R_(b) may togetherform a heterocyclo or heteroaryl ring. It should be understood that whena substituted alkyl group is substituted with an aryl, cycloalkyl,heteroaryl, or heterocyclo, such rings are as defined below and thus mayhave one to three substituents as set forth below in the defintions forthese terms.

[0046] When the term “alkyl” is used as a suffix following anotherspecifically named group, e.g., arylalkyl, heteroarylalkyl, the termdefines with more specificity at least one of the substituents that thesubstituted alkyl will contain. For example, arylalkyl refers to an arylbonded through an alkyl, or in other words, a substituted alkyl grouphaving from 1 to 12 carbon atoms and at least one substituent that isaryl (e.g., benzyl or biphenyl). “Lower arylalkyl” refers to substitutedalkyl groups having 1 to 4 carbon atoms and at least one arylsubstituent.

[0047] The term “alkenyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one doublebond. Alkenyl groups of 2 to 6 carbon atoms and having one double bondare most preferred.

[0048] The term “alkynyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one triplebond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bondare most preferred. A substituted alkenyl or alkynyl will contain one,two, or three substituents as defined above for alkyl groups.

[0049] The term “alkylene” refers to bivalent straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, e.g., {—CH₂—}_(n), wherein n is 1 to 12, preferably 1-8. Loweralkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, aremost preferred. The terms “alkenylene” and “alkynylene” refer tobivalent radicals of alkenyl and alknyl groups, respectively, as definedabove. Substituted alkylene, alkenylene, and alkynylene groups may havesubstituents as defined above for substituted alkyl groups.

[0050] The term “alkoxy” refers to the group OR_(e) wherein R_(e) isalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, heterocycle, or cycloalkyl. Thus, an alkoxyincludes such groups as methoxy, ethoxy, cyclopropyloxy,pyrrolidinyloxy, and so forth. The term “aryloxy” refers to the groupsO(aryl) or O(heteraryl), wherein aryl and heteroaryl are as definedbelow.

[0051] The term “alkylthio” refers to an alkyl or substituted alkylgroup as defined above bonded through one or more sulfur (—S—) atoms,e.g., —S (alkyl) or —S (alkyl-R_(a)).

[0052] The term “alkylamino” refers to an alkyl or substituted alkylgroup as defined above bonded through one or more nitrogen (—NR_(f)—)groups, wherein R_(f) is hydrogen, alkyl, substituted alkyl, orcycloalkyl.

[0053] The term “acyl” refers to an alkyl or substituted alkyl group asdefined above bonded through one or more carbonyl {—C(═O)—} groups. Whenthe term acyl is used in conjunction with another group, as inacylamino, this refers to the carbonyl group {—C(═O) } linked to thesecond named group. Thus, acylamino refers to —C(═O)NH₂, substitutedacylamino refers to the group —C(═O)NRR, and acylaryl refers to—C(═O)(aryl).

[0054] The term “aminoacyl” refers to the group —NR_(f)C(═O)R_(g),wherein R_(g) is hydrogen, alkyl, or substituted alkyl, and R_(f) is asdefined above for alkylamino groups.

[0055] The term “halo” or “halogen” refers to chloro, bromo, fluoro andiodo.

[0056] The term “carboxy” when used alone refers to the group CO₂H.Carboxyalkyl refers to the group CO₂R, wherein R is alkyl or substitutedalkyl.

[0057] The term “sulphonyl” refers to a sulphoxide group (i.e.,—S(O)₁₋₂—) linked to an organic radical including an alkyl, alkenyl,alkynyl, substituted alkyl, substituted alkenyl, or substituted alkynylgroup, as defined above. The organic radical to which the sulphoxidegroup is attached may be monovalent (e.g., —SO₂-alkyl), or bivalent(e.g., —SO₂-alkylene, etc.)

[0058] The term “amidino” refers to the group

[0059] and the term “guanidino” refers to the group

[0060] wherein for each of amidino and guanidino R_(h), R_(i), and R_(j)may be hydrogen, alkyl, or substituted alkyl, or any two of R_(h),R_(i), and R_(j) may join to form a heterocyclo or heteroaryl ring withthe other of R_(h), R_(i), and R_(j) comprising hydrogen, alkyl, orsubstituted alkyl.

[0061] The term “cycloalkyl” refers to substituted and unsubstitutedmonocyclic or bicyclic hydrocarbon groups of 3 to 9 carbon atoms whichare, respectively, fully saturated or partially unsaturated, including afused aryl ring, for example, an indan. A cycloalkyl group may besubstituted by one or more (such as one to three) substituents selectedfrom alkyl, substituted alkyl, aminoalkyl, halogen, cyano, nitro,trifluoromethyl, hydroxy, alkoxy, alkylamino, sulphonyl, —SO₂(aryl),—CO₂H, —CO₂-alkyl, —C(═O)H, keto, —C(═O)—(CH₂)₁₋₂NH₂,—C(═O)—(CH₂)₁₋₂NH(alkyl), —C(═O)—(CH₂)1-2N(alkyl)₂, acyl, aryl,heterocylcle, heteroaryl, or another cycloalkyl ring of 3 to 7 carbonatoms. The term “cycloalkylene” refers to a cycloalkyl forming a link orspacer between two other groups, i.e., a cycloalkylene is a cycloalkylthat is bonded to at least two other groups. The term cycloalkylincludes saturated or partially unsaturated carbocyclic rings having acarbon-carbon bridge of three to four carbon atoms or having a benzenering joined thereto. When the cycloalkyl group is substituted with afurther ring, said further ring may have one to two substituentsselected from R_(k), wherein R_(k) is lower alkyl, hydroxy, loweralkoxy, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,and lower alkyl e substituted with one to two hydroxy, lower alkoxy,amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, and/or nitro.

[0062] The term “aryl” refers to substituted and unsubstituted phenyl,1-naphthyl and 2-naphthyl, with phenyl being preferred. The aryl mayhave zero, one, two or three substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo,hydroxy, nitro, cyano, amino, trifluoromethyl, trifluoromethoxy,sulphonyl, —SO₂(aryl), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy,acyl, —C(═O)H, —C(═O)phenyl, —CO₂-alkyl, cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁ ₂NH₂, —C(═O)—(CH₂)₁ ₂NH(alkyl),—C(═O)-(CH₂)₁ ₂N(alkyl)₂, phenyl, benzyl, phenylethyl, phenyloxy,phenylthio, heterocyclo, heteroaryl, or a C₃₋₇cycloalkyl ring. The term“arylene” refers to an aryl as defined above forming a link or spacerbetween two other groups, i.e., an arylene is an aryl that is bonded toat least two other groups. When the aryl group is substituted with afurther ring, said further ring may have one to two substituentsselected from R_(k), wherein R_(k) is defined as above.

[0063] The term “carbocyclo” or “carbocyclic” refers to a cyclic groupin which all ring atoms are carbon, including optionally-substitutedcycloalkyl and aryl groups, as defined herein.

[0064] The term “heterocyclo” or “heterocycle” refers to substituted andunsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to 11membered bicyclic groups, and 10 to 15 membered tricyclic groups whichhave at least one heteroatom (O, S or N) in at least one of the rings.Each ring of the heterocyclo group containing a heteroatom can containone or two oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom. The fused rings completing the bicyclic and tricyclic groups maycontain only carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quatemized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclo ring may contain one, two or three substituents selectedfrom the group consisting of halo, amino, cyano, alkyl, substitutedalkyl, trifluoromethyl, trifluoromethoxy, sulphonyl, —SO2(aryl),—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy, alkylthio, hydroxy,nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, carboxy,—CO₂-alkyl, cycloalkyl, —C(═O)H, acyl, —(C═O)NH₂, —(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁ ₂NH₂, —C(═O)—(CH₂)₁₋₂NH(alkyl),—C(═O)—(CH₂)1-2N(alkyl)₂, heterocyclo, heteroaryl, a C₃₋₇cycloalkylring. keto, ═N—OH, ═N—O-lower alkyl, or a five or six membered ketal,i.e., 1,3-dioxolane or 1,3-dioxane. The heterocyclo ring may have asulfur heteroatom that is substituted with one or more oxygen (═O)atoms, as for example, in

[0065] The term “heterocyclene” refers to a heterocycle as defined aboveforming a link or spacer between two other groups. When the heterocyclogroup is substituted with a further ring, said further ring may have oneto two substituents selected from R_(k), wherein R_(k) is defined asabove.

[0066] Exemplary monocyclic groups include azetidinyl, pyrrolidinyl,oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

[0067] The term “heteroaryl” refers to substituted and unsubstitutedaromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclicgroups, and 11 to 14 membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicand tricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain one, two or three substituentsselected from the group consisting of halo, amino, cyano, alkyl,substituted alkyl, trifluoromethyl, trifluoromethoxy, sulphonyl,—SO2(aryl), —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy, alkylthio,hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,carboxy, —CO₂-alkyl, cycloalkyl, —C(═O)H, acyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂-carboxy,—NH—CH₂—CO₂-alkyl, —C(═O)—(CH₂)₁₋₂NH₂, —C(═O)—(CH₂)₁₋₂NH(alkyl),—C(═O)—(CH₂)₁₋₂N(alkyl)₂, heterocylco, heteroaryl, or a C₃₋₇cycloalkylring. The heterocyclo ring may have a sulfur heteroatom that issubstituted with one or more oxygen (═O) atoms, as for example, in

[0068] The term “heteroarylene” or “heterarylene” refers to a heteroarylas defined above forming a link or spacer between two other groups,i.e., it is a heteroaryl that is bonded to at least two other groups.When the heteroaryl group is substituted with a further ring, saidfurther ring may have one to two substituents selected from R_(k),wherein R_(k) is defined as above.

[0069] Exemplary monocyclic heteroaryl groups include pyrrolyl,pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0070] Exemplary bicyclic heteroaryl groups include indolyl,benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

[0071] Exemplary tricyclic heteroaryl groups include carbazolyl,benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl andthe like.

[0072] When reference is made herein to a particularly-namedheterocyclic or heteroaryl group, such as azetidinyl, imidazolyl,piperazinyl, and so forth, the named ring may optionally contain one ormore (preferably one to three) substituents selected from thesubstituents recited above for heteroaryl and heterocyclo groups, asappropriate. The term azetidinyl refers to an optionally-substitutedfour membered ring having one nitrogen heteroatom, i.e.,

[0073] wherein R can be any substituent defined herein for heterocyclogroups and unless otherwise stated, the azetidinyl ring can be ttachedto another group at any available carbon atom or at the nitrogen atom.

[0074] When reference is made to a particularly-named group having atleast one heterocyclo, heteroaryl, or carbocyclic ring “joined” thereto,it is meant that two substituents attached to the same, adjacent, ornon-adjacent atoms of the particularly-named group may join to form asecond or third ring (i.e., the further ring may be fused, bridged orattached in a spiro fashion.) Each ring of these bicyclic or tricyclicgroups may be optionally substituted, wherein the substituents areselected from those recited above for cycloalkyl, aryl, heterocyclo andheteroaryl groups. Thus, an imidazole having at least one ring joinedthereto may include an aryl-fused imidazole such as benzimidazole havingone or more (preferably one to three substituents), to anheteroaryl-fused imidazole such as a pyridoimidazole having one or more(preferably one to three) substituents, and so forth.

[0075] Accordingly, the above definitions and optional substituents forcycloalkyl, heterocyclo, and heteroaryl groups apply to spirocyclic ringsystems. To illustrate, in compounds of formula (D) above, R₈ and R₉ arerecited as optionally forming a spirocyclic ring. Thus, when z is 1, R₈and R₉ together with the group E to which they are attached may beselected from the following exemplary groups, among others:

[0076] in which each R₃₂ group is hydrogen or selected from theabove-recited substituents for aryl, cycloalkyl, heterocyclo andheteroaryl groups.

[0077] Additionally, one skilled in the field may make appropriatesubstitutions for the various groups of compounds of formula (I) herein,without departing from the spirit and scope of the invention. Forexample, it will be appreciated that in compounds of formula (I), thegroup E can be selected from, or replaced with, groups such as,

[0078] as defined in WO 02/00654 and WO 01/91752, wherein the variousgroups R, A, G₁₋₃, Q, W, X, Y, Z, d, e, f, n and w, may be selected fromgroups recited in WO 02/00654 and/or WO 01/91752, incorporated herein byreference.

[0079] Throughout the specification, groups and substituents thereof maybe chosen to provide stable moieties and compounds.

[0080] The compounds of formula I form salts which are also within thescope of this invention. Reference to a compound of the formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as, but not limited to an amine or a pyridine or imidazole ring,and an acidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also comtemplated as within the scope of the invention,e.g., they may be useful in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula I maybe formed, for example, by reacting a compound of the formula I with anamount of acid or base, such as an equivalent amount, in a medium suchas one in which the salt precipitates or in an aqueous medium followedby lyophilization.

[0081] The compounds of formula I which contain a basic moiety, such as,but not limited to an amine or a pyridine or imidazole ring, may formsalts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

[0082] The compounds of formula I which contain an acidic moiety, suchas, but not limited to a carboxylic acid, may form salts with a varietyof organic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines [formed withN,N-bis(dehydro-abietyl)ethylenediamine], N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g., benzyl and phenethylbromides), and others.

[0083] Prodrugs and solvates of the compounds of this invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, and/or a salt and/or solvate thereof. Solvates of thecompounds of formula I are preferably hydrates.

[0084] Compounds of the formula I and salts thereof may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

[0085] All stereoisomers of the present compounds, such as those, forexample, which may exist due to asymmetric carbons, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons) and diastereomeric forms, are contemplated and within the scopeof this invention. Individual stereoisomers of the compounds of thisinvention may, for example, be substantially free of other isomers, ormay be admixed, for example, as racemates or with all other or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations.

Methods of Preparation

[0086] The compounds of the present invention may be prepared by methodssuch as those illustrated in the following Schemes I to III. Startingmaterials are commercially available or can be readily prepared by oneof ordinary skill in the art using known methods. For all of the schemesand compounds, the designated groups such as E, W, R₈, R₉, etc., are asdescribed herein for a compound of formula I, unless otherwiseindicated.

[0087] Solvents, temperatures, pressures, and other reaction conditionsmay readily be selected by one of ordinary skill in the art. Startingmaterials are commercially available or readily prepared by one ofordinary skill in the art. High Speed Analoging (HSA) may be employed inthe preparation of compounds, for example, where the intermediatespossess a carboxylic acid or amino group.

[0088] Compounds of formula (Ib) can be prepared from compounds (Ia)[wherein P* is an amino protecting group, such as -Boc-, -CBZ-, -Fmoc-,which can be present in Q as in formula (Ia) or independently bonded toQ] via an appropriate amine deprotection process in an inert solvent ata temperature in the range −10° C. to 100° C. The choice of deprotectionroutes can be chosen by one of ordinary skill in the art. They include,but are not limited to TFA or hydrogen chloride acid for -Boc-,hydrogenation with an appropriate metal catalyst (such as Pd), for-CBZ-, or a base, such as NMM or DEA, for -Fmoc-. Inert solventsinclude, but are not limited to methylene dichloride, alcoholicsolvents, THF, acetic acid, DMF, acetonitrile, and dioxane.

[0089] Compounds of formula (Ia) can be prepared by the coupling ofcompounds of formula (5) with compounds (4) using an appropriatecarboxylic acid activating reagent in an inert solvent. Exemplarycarboxylic acid activating agents include carbonyldiimidazole,dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activatingagents known by one of ordinary skill in the art. Exemplary inertsolvents include ethers, including THF and dioxane, DMF, acetonitrile,or CH₂Cl₂.

[0090] Compounds (4) can be prepared by the hydrolysis of compounds (3)using a hydroxide source. Exemplary hydroxide sources include NaOH orLiOH. Exemplary solvents include water, alcohols, and mixtures ofethers/water.

[0091] Compounds (3) can be prepared by the coupling of compounds (1)and (2) using an appropriate carboxylic acid activating reagent in aninert solvent. Exemplary carboxylic acid activating agents includecarbonyldiimidazole, dicyclohexylcarbodiimide, pentofluorophenoltrifluoroacetate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, orother activating agents known by one of ordinary skill in the art.Exemplary inert solvents include ethers, including THF and dioxane, DMF,acetonitrile, or CH₂Cl₂.

[0092] Compounds (1), (2) and (3) are either commercially available oravailable by methods known to one of ordinary skill in the art.

[0093] Compounds of formula (Ib) can be prepared from compounds offormula (Ia) [wherein P* is an amino-protecting group as in Scheme I]via an appropriate amine deprotection process in an inert solvent at atemperature in the range from −10° C. to 100° C. The choice ofdeprotection routes can be chosen by one of ordinary skill in the art.They include, but are not limited to TFA or hydrogen chloride acid for-Boc-, hydrogenation with an appropriate metal catalyst for -CBZ-, or abase, such as NMM or DEA, for —Fmoc—. Inert solvents include, but arenot limited to methylene dichloride, alcoholic solvents, THF, aceticacid, DMF, acetonitrile, and dioxane.

[0094] Compounds of formula (Ia) can be prepared by the coupling ofcompounds (8) and (9) using an appropriate carboxylic acid activatingreagent in an inert solvent. Exemplary carboxylic acid activating agentsinclude carbonyldiimidazole, dicyclohexylcarbodiimide, pentofluorophenoltrifluoroacetate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, orother activating agents known by on of ordinary skill in the art.Exemplary inert solvents include ethers, including THF and dioxane, DMF,acetonitrile, or CH₂Cl₂.

[0095] Compounds (8) [wherein P* is an amino-protecting group as above]can be prepared from compounds (7) via an appropriate amine deprotectionprocess in an inert solvent at temperatures ranging from −10° C. to 100°C. The choice of deprotection routes can be chosen by one of ordinaryskill in the art and include those referenced above in Scheme I for-Boc-, -CBZ-, and -Fmoc-. Inert solvents include, but are not limited tomethylene dichloride, alcoholic solvents, THF, acetic acid, DMF,acetonitrile, and dioxane.

[0096] Compounds (7) can be prepared by the coupling of compounds (5)and (6) using an appropriate carboxylic acid activating reagent in aninert solvent. Exemplary carboxylic acid activating agents includecarbonyldiimidazole, dicyclohexylcarbodiimide, pentofluorophenoltrifluoroacetate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, orother activating agents known by one of ordinary skill in the art.Exemplary inert solvents include ethers, including THF and dioxane, DMF,acetonitrile, or CH₂Cl₂.

[0097] Compounds (5) and (6) are either commercially available oravailable by methods known to one of ordinary skill in the art.

[0098] Compounds of formula (If) can be prepared from compounds offormula (Ie) [wherein P* is an amino protecting group as in Scheme I]via an appropriate amine deprotection process chosen by one of ordinaryskill in the art, such as described above in Schemes I and II.

[0099] Compounds of formula (Ie) can be prepared by the coupling ofcompounds of formula (Id) with amines of the formula R₂₅R₂₆NH using anappropriate carboxylic acid activating reagent in an inert solvent.Exemplary carboxylic acid activating agents include carbonyldiimidazole,dicyclohexylcarbodiimide, pentofluorophenol trifluoroacetate,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or other activatingagents known by one of ordinary skill in the art. Exemplary inertsolvents include ethers, including THF and dioxane, DMF, acetonitrile,or CH₂Cl₂.

[0100] Compounds of formula (Id) can be prepared by the hydrolysis ofcompounds of formula (Ic) using a hydroxide source. Exemplary hydroxidesources include NaOH or LiOH. Exemplary solvents include water,alcohols, and mixtures of ethers/water.

[0101] Amines of the formula R₁₃R₁₄NH are either commercially availableor available by methods known to one of ordinary skill in the art.Compounds of formula (Ic) can be prepared as described above in SchemesI and II.

[0102] All documents cited in the present specification are incorporatedherein by reference in their entirety.

Preferred Compounds

[0103] Preferred compounds are those having the formula,

[0104] and pharmaceutically-acceptable salts, hydrates, or prodrugsthereof, in which:

[0105] X is N or CH;

[0106] R₁ is hydrogen or C₁₋₆alkyl or is taken together with R₂ or R₃ toform a monocyclic or bicyclic heteroaryl or heterocycle;

[0107] R₂ is hydrogen, aryl, cycloalkyl, heteroaryl, heterocyclo, orC₁₋₆alkyl or C₂₋₆alkenyl optionally substituted with one to three ofhydroxy, halogen, aryl, cycloalkyl, heteroaryl, and/or heterocyclo; orR₂ is taken together with R₁ or R₃ to form a monocyclic or bicyclicaryl, cycloalkyl, heteroaryl or heterocycle;

[0108] R₃ is hydrogen or C₁₋₆alkyl or is taken together with R₂ to forma monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle;

[0109] E is E₁, E₂, E₃, or E₄, wherein

[0110] E₄ is —NR₁₁R₁₂;

[0111] G is selected from:

[0112] a) C₂₋₆alkenyl optionally substituted with phenyl;

[0113] b) —OR, 8, —C(═O)R₁₈, —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉,—NR₁₈CO₂R₁₉, —NR₁₈SO₂R₁₇, —SO₂R₁₇, —NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈,

[0114] c) C₁₋₆alkyl or C₂₋₆alkenyl (straight or branched chain)substituted with at least one of cyano, —OR₁₇, —C(═O)R₁₈, —CO₂R₁₈,—C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, —NR₁₈CO₂R₁₉, —NR₁₈SO₂R₁₇, —SO₂R₁₇,—NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈; and

[0115] d) when y is 0, G also may be selected from pyrrolidinyl,piperidinyl, pyrrolidinylalkyl, and piperidinylalkyl;

[0116] W is selected from —NR₂₁R₂₂, —OR₂₃, —NR₂₁C(═O)R₂₄, —NR₂₁CO₂R₂₄,amidino, guanidino, or a substituted or unsubstituted heterocyclo,heteroaryl, or cycloalkyl group selected from azetidinyl, imidazolyl,imidazolidinyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl,1,2-dihydropyridazinyl, pyranyl, tetrahydropyranyl, piperazinyl,homopiperazinyl, pyrrolyl, pyrrolidinyl, piperidinyl, thiazolyl,tetrahydrothiazolyl, thienyl, furyl, tetrahydrofuryl, morpholinyl,isoquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, oxazolyl,tetrahydro-oxazolyl, and C₃₋₇cycloalkyl, wherein said heteroaryl,heterocyclo or cycloalkyl groups may additionally have joined thereto anoptionally substituted five-to-seven membered heterocyclic, heteroaryl,or carbocyclic ring;

[0117] R₄ and R₇ are independently selected from hydrogen, alkyl,substituted alkyl, halogen, hydroxy, alkoxy, and keto;

[0118] R₅, R_(5a), R_(5b), R₆, R_(6a), R_(6b), R₈ and R₉ areindependently hydrogen, halogen, cyano, alkyl, substituted alkyl,alkenyl, hydroxy, alkoxy, alkoxycarbonyl, acyl, cycycloalkyl,heterocyclo, aryl, or heteroaryl; or R_(5a) and R_(5b), R_(6a) andR_(6b), or R₈ and R₉ taken together form a keto group (═O) or amonocyclic or bicyclic cycloalkyl or heterocyclo joined in a spirofashion to ring E, or alternatively, R_(5a) and/or R_(5b) together withR₈ and/or R₉, or R_(6a) and/or R_(6b) together with R₈ and/or R₉, aretaken to form a fused benzene or heterocyclo ring; provided that, when Gis a C₁₋₆alkyl substituted with —OR₁₇, —CO₂R₁₈, or —C(═O)NR₁₈R₁₉, thenR_(5a), R_(5b), R_(6a), and R_(6b) are hydrogen;

[0119] R₁₀ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl, and hetereocyclo;

[0120] R₁₁ is hydrogen or C₁₋₈alkyl;

[0121] R₁₂ is C₁₋₈alkyl, substituted C₁₋₈alkyl, or cycloalkyl;

[0122] R₁₇ is alkyl, substituted alkyl (e.g., benzyl), cycloalkyl, aryl,heterocyclo, or heteroaryl;

[0123] R₁₈, R₁₉, and R₂₀ are independently selected from hydrogen,alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, heterocyclo, C(═O)R₂₈ or aC₁₋₄alkyl or C₂₋₄alkenyl substituted with one or more of aryl,heteroaryl, cycloalkyl, heterocyclo, alkoxycarbonyl, phenyloxy, andbenzyloxy, and each of said ringed groups of R₁₈, R₁₉, and R₂₀ in turnis optionally substituted with one to two R₃₆;

[0124] R₂₁ and R₂₂ are selected from hydrogen, alkyl and substitutedalkyl;

[0125] R₂₃ and R₂₄ are independently hydrogen, alkyl, substituted alkyl,aryl, heteroaryl, heterocyclo, and cycloalkyl;

[0126] R₂₈ is hydrogen, alkyl, or substituted alkyl;

[0127] R₃₆ is halogen, methoxy, nitro, phenyl, phenyloxy, or alkylamino;

[0128] n is 0, 1, 2, 3 or 4;

[0129] r and s are 0 or 1;

[0130] x is 0, 1, or 2;

[0131] y is 0, 1, 2, 3 or 4; and

[0132] z is 0, 1, or 2.

[0133] In compounds of formula (I), preferably G is selected fromC₂₋₆alkenyl optionally substituted with phenyl; —OR₁₇, —C(═O)R₁₈,—CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, —NR₁₈CO₂R₁₉, —SO₂R₁₇,—NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈; and C₁₋₆alkyl or C₂₋₆alkenyl (straight orbranched chain) substituted with at least one of cyano, —OR₁₇,—C(═O)R₁₈, —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, —NR₁₈CO₂R₁₉, —SO₂R₁₇,or —NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈; and when y is O, G also preferably maybe selected from pyrrolidinyl, piperidinyl, pyrrolidinylalkyl, andpiperidinylalkyl, wherein R₁₇ is lower alkyl, or optionally substitutedphenyl or benzyl; R₁₈ and R₁₉ are as defined above, but preferably arehydrogen, lower alkyl, or optionally substituted phenyl or benzyl; andR₂₀ is hydrogen or lower alkyl.

[0134] More preferred are compounds where G is —C₂₋₄alkenyl, —NHSO₂R₁₇,or —NHC(═O)R₁₉, wherein R₁₇ and R₁₉ are lower alkyl or phenyl, or when Wis imidazolyl, R₁₉ is taken together with W to form a heterocyclo ring.Most preferred are compounds where G is NHC(═O)CH₃.

[0135] In compounds of formula (I) herein, preferably W is selected from

[0136] —NR₂₁R₂₂, NR₂₁C(═O)R₂₄, and imidazolyl, wherein R₂₁, and R₂₂ arehydrogen or lower alkyl; R₃₄ is C₁₋₄alkyl; and u is 0 or 1. Morepreferably W is —NH₂, NH(lower alkyl), N(lower alkyl)₂, imidazolyl, or.

[0137] wherein R₃₄ is hydrogen or lower alkyl.

[0138] More preferred are compounds having the formula,

[0139] wherein K is phenyl or thiazolyl, G is —NR₁₈C(═O)R₁₉, and R₁₈ andR₁₉ are hydrogen, lower alkyl, or phenyl; W is —NH₂, NH(lower alkyl),N(lower alkyl)₂, imidazolyl or

[0140] wherein R₃₄ is hydrogen or lower alkyl; y is 0, 1, 2, 3 or 4,more preferably 1; R₃₀ is selected from C₁₋₄alkyl, hydroxy, alkoxy,halogen, nitro, cyano, amino, alkylamino, phenyl, and acylphenyl, morepreferably chloro or methoxy; and E is a group selected from El, E₂, E₃,or E₄, recited above, but more preferably is

[0141] Further preferred compounds are those having the formulae,

[0142] and pharmaceutically-acceptable salts, hydrates, and prodrugsthereof.

Utility

[0143] The inventive compounds are modulators of the melanocortinreceptors MC-1R, MC-3R, MC-4R, and/or MC-5R. The compounds are useful intreating a wide range of conditions responsive to regulation of themelanocortin receptors, including inflammatory and immune diseases,cardiovascular diseases, skin conditions, neurodegenerative conditions,sexual dysfunction, bodyweight disorders, and cancer. Certain compoundsaccording to the invention have selective affinity for one melanocortinreceptor relative to the other melanocortin receptors and thus areparticularly useful for treating those diseases responsive to regulationof that receptor. For example, certain compounds have high selectivityfor binding to MC-1R relative to MC-3R, MC-4R, and MC-5R, and thosecompounds are particularly useful in treating inflammatory or immuneconditions. Certain other compounds according to the invention have highselective affinity for MC-4R and are particularly useful in treatingbodyweight and/or neurodegenerative disorders. As used herein, the term“treating” or “treatment” refers to prophylaxis measures designed toinhibit or delay the onset of the disease or disorder and to responsivemeasures to alleviate, ameliorate, lessen, or cure the disease ordisorder and/or its symptoms.

[0144] Compounds of the invention may be used to treat inflammation,particularly inflammation characterized by the activation of NF-κBand/or release of inflammatory cytokines. The compounds can beimmunomodulators and have multiple effects on cells of the immunesystem. The compounds may be used to increase the levels of cAMP incells (with resultant anti-inflammatory effects), decrease levels of thepro-inflammatory messenger nitric oxide, decrease chemotactic ability,and alter the expression of immune-related genes for such agents ascytokines, adhesion molecules, and nitric oxide synthase.

[0145] In view of their effects on inhibiting NF-κB activity andsuppressing cytokine accumulation, the compounds will be useful intreating consequences of many diseases associated with chronic and acuteinflammation and immune-modulation. Such diseases include, but are notlimited to, inflammatory bowel disease, irritable bowel syndrome, gallbladder disease, Chrohn's disease, rheumatoid arthritis, osteoarthritis,osteoporosis, traumatic arthritis, rubella arthritis, muscledegeneration, pancreatis (acute or chronic), psoriasis,glomerulonephritis, serum sickness, lupus (systematic lupuserythematosis), urticaria, scleraclerma, schleroderma, chronicthyroiditis, Grave's disease, dermatitis (contact or atopic),dermatomyositis, alopecia, atopic eczemas, ichthyosis, fever, sepsis,migraine, cluster headaches, Alzheimer's Disease, Parkinson's disease,Creutzfeldt-Jacob disease, multiple sclerosis, tuberculosis, dementia,and transplant or graft-host rejections (e.g., kidney, liver, heart,lung, pancreas, bone marrow, cornea, small bowel, skin allografts, skinhomografts and heterografts, etc.). The compounds may also be used totreat respiratory allergies and diseases including asthma, acuterespiratory distress syndrome, hayfever, allergic rhinitis, and chronicobstructive pulmonary disease; and inflammatory disorders of the centralnervous system, including HIV encephalitis, cerebral malaria,meningitis, and ataxia telangiectasis. Additionally, the compounds maybe useful in treating pain, e.g., post-operative pain, neuromuscularpain, headache, pain caused by cancer, dental pain, and arthritis pain.

[0146] In view of their activity in inhibiting NF-κB activity, thecompounds may be used to treat viral and autoimmune diseases includingherpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2),cytomegalovirus, Epstein-Barr, human immunodeficiency virus (HIV),Addison's disease (autoimmune disease of the adrenal glands), idiopathicadrenal insufficiency, autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome), chronic active hepatitis or acutehepatitis infection (including hepatitis A, hepatits B, and hepatitisC), autoimmune gastritis, autoimmune hemolytic anemia, and autoimmuneneutropenia. The compounds of the invention may also be used to treatfungal infections such as mycosis fungoides.

[0147] In addition, the compounds of this invention are useful intreating diseases of the cardiovascular system including those diseasesin which inflammation is an underlying component. These diseases includebut are not limited to atherosclerosis, transplant atherosclerosis,peripheral vascular disease, inflammatory vascular disease, intermittentclaudication, restenosis, cerebrovascular stroke, transient ischemicattack, myocardial ischemia and myocardial infarction. The compoundsalso may be used to treat hypertension, hyperlipidemia, coronary arterydisease, unstable angina, thrombosis, thrombin-induced plateletaggregation, and/or consequences occurring from thrombosis and/or theformation of atherosclerotic plaques.

[0148] Additionally, the compounds may be useful to treat stroke andother ischemic brain diseases and/or neurodegeneration associatedtherewith, and the neurodegeneration of, or consequences of, traumaticbrain injury.

[0149] In view of their ability to act as immunomodulators in the skinand affect the production of melanin in the skin, the compounds areuseful in altering pigmentation in the skin and may be used asphotoprotective agents including agents for preventing, treating, orameliorating sunburn. The compounds also may be used in treating acne,vitiligo, alopecia arreata, photosensitivity disorders, albinism, andporphyria. Addditionally, the compounds are useful to promote cosmeticas well as therapeutic tanning.

[0150] The compounds of the invention may also be used to treatneurodegenerative disorders including depression, anxiety, compulsion(obsessive-compulsive disorder), neuroses, psychosis, insomnia/sleepdisorder, sleep apnea, and drug or substance abuse.

[0151] The compounds of the invention may be used to treat male orfemale sexual dysfunction. Male sexual dysfunction includes impotence,loss of libido, and erectile dysfunction (including but not limited toejaculatory failure, premature ejaculation, or an inability to achieveor maintain an erection or inability to achieve an orgasm). Femalesexual dysfunction may include sexual arousal disorder or disordersrelating to desire, sexual receptivity, orgasm, and/or disturbances intrigger points of sexual function. Female sexual dysfunction may alsoinclude sexual pain, premature labor, dysmenorrhea, excessivemenstruation, and endometriosis.

[0152] The compounds of the invention may also be used to treatbodyweight disorders including but not limited to obesity and anorexia(e.g., by altering appetite, metabolic rate, fat intake or carbohydratecraving); and diabetes mellitus (by enhancing glucose tolerance and/ordecreasing insulin resistance).

[0153] The compounds also may be used to treat cancer, moreparticularly, cancer of the lung, prostate, colon, breast, ovaries, andbone, or angiogenic disorders including the formation or growth of solidtumors.

[0154] The compounds of the invention may also be used to treatveterinary disease such as veterinary viral infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

[0155] The term “melanocortin-receptor associated condition” when usedherein refers to each of the above-referenced conditions, disorders, ordiseases that may be treated by agonizing or antagonizing a melanocortinreceptor, inhibiting NF-κB activity and/or suppressing cytokineaccumulation as if each of these conditions, disorders and diseases wereset forth herein at length.

[0156] The inventive compounds may be used alone or in combination witheach other and/or other therapeutic agents such as anti-inflammatorydrugs, antibiotics, anti-viral agents, anti-fungal agents, anti-diabeticagents, anti-osteoporosis agents, anti-obesity agents or appetitesuppressants, growth promoting agents (including growth hormonesecretagogues), anti-anxiety agents, anti-depressants, anti-hypertensiveagents, cholesterol/lipid lowering agents, bone resorption inhibitors,and anti-tumor agents including antiproliferative agents, or cytotoxicdrugs.

[0157] Examples of suitable other anti-inflammatory agents with whichthe inventive compounds may be used include aspirin, non-steroidalantiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin), TNF-αinhibitors (such as tenidap and rapamycin or derivatives thereof), orTNF-α antagonists (e.g., infliximab, OR1384), prednisone, dexamethasone,Enbrel®, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitorssuch as Naproxen®, Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists,CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate(CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1,prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein,kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, therapies for the treatment of irritable bowel syndrome(e.g., Zelmac® and Maxi-K® openers such as those disclosed in U.S. Pat.No. 6,184,231 B1), or other NF-κB inhibitors, such as corticosteroids,calphostin, CSAIDs, 4-substituted imidazo [1,2-A]quinoxalines asdisclosed in U.S. Pat. No. 4,200,750; Interleukin-10, glucocorticoids,salicylates, nitric oxide, and other immunosuppressants; and nucleartranslocation inhibitors, such as deoxyspergualin (DSG). To treat painsuch as migraine and other headaches, the inventive compounds may beused in combination with aspirin, NSAIDs, or with 5-HT_(ID) receptoragonists such as sumitriptan, eletriptan or rizatriptan.

[0158] Examples of suitable other antibiotics with which the inventivecompounds may be used include β-lactams (e.g., penicillins,cephalosporins and carbopenams); β-lactam and lactamase inhibitors(e.g., augamentin); aminoglycosides (e.g., tobramycin and streptomycin);macrolides (e.g., erythromycin and azithromycin); quinolones (e.g.,cipro and tequin); peptides and deptopeptides (e.g. vancomycin, synercidand daptomycin) metabolite-based anti-biotics (e.g., sulfonamides andtrimethoprim); polyring systems (e.g., tetracyclins and rifampins);protein synthesis inhibitors (e.g., zyvox, chlorophenicol, clindamycin,etc.); and nitro-class antibiotics (e.g., nitrofurans andnitroimidazoles).

[0159] Examples of suitable other antifungal agents with which theinventive compounds may be used include fungal cell wall inhibitors(e.g., candidas), azoles (e.g., fluoconazole and vericonazole), andmembrane disruptors (e.g., amphotericin B).

[0160] Examples of suitable other antiviral agents for use with theinventive compounds include nucleoside-based inhibitors, protease-basedinhibitors, and viral-assembly inhibitors.

[0161] Examples of suitable anti-diabetic agents for use in combinationwith the compounds of the present invention include biguanides (e.g.,metformin or phenformin), glucosidase inhibitors (e.g,. acarbose ormiglitol), insulins (including insulin secretagogues, sensitizers ormimetics), meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, gliclazide, chlorpropamide and glipizide),biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones(e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alphaagonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2inhibitors, glycogen phosphorylase inhibitors, inhibitors of fatty acidbinding protein (aP2), glucagon-like peptide-1 (GLP-1); dipeptidylpeptidase IV (DP4) inhibitors, Alistat@, Meridia®, and Zenacol®.

[0162] Examples of suitable anti-osteoporosis agents for use incombination with the compounds of the present invention includealendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin,RANK ligand antagonists, calcium sensing receptor antagonists, TRAPinhibitors, selective estrogen receptor modulators (SERM) and AP-1inhibitors.

[0163] Examples of suitable anti-obesity agents for use in combinationwith the compounds of the present invention include aP2 inhibitors, PPARgamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, suchas AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) orother known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor, suchas orlistat or ATL-962 (Alizyme), a serotonin, adrenergic (and dopamine)reuptake inhibitor, such as sibutramine, topiramate (Johnson & Johnson)or axokine (Regeneron), other thyroid receptor beta drugs, such as athyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an anorectic agent(such as dexamphetamine, phentermine, phenylpropanolamine or mazindol).Additionally, the inventive compounds may be used with an α-gluocosidaseinhibitor, an MHG—CoA reductase inhibitor, a sequestrant chlolestorallowering agent, a β3 adrenergic receptor agonist, a neuropeptide Yantagonist, or an α2-adrenergic receptor antagonist.

[0164] A still further use of the compounds of the invention is incombination with estrogen, testosterone, a selective estrogen receptormodulator, such as tamoxifen or raloxifene, or other androgen receptormodulators.

[0165] A further use of the compounds of this invention is incombination with steriodal or non-steroidal progesterone receptoragonists (“PRA”), such as levonorgestrel, medroxyprogesterone acetate(MPA).

[0166] Examples of suitable anti-anxiety agents for use in combinationwith the compounds of the present invention include benzodiazepines,diazepam, lorazepam, buspirone (Serzone®), oxazepam, and hydroxyzinepamoate, or dopamine recetpor agonists.

[0167] Examples of suitable anti-depressants for use in combination withthe compounds of the present invention include citalopram, fluoxetine,nefazodone, sertraline, and paroxetine.

[0168] In treating skin disorders or diseases as described above, thecompounds may be used alone or in combination with a retinoid, such astretinoin, or a vitamin D analog.

[0169] Examples of suitable anti-hypertensive agents for use incombination with the compounds of the present invention include betaadrenergic blockers, calcium channel blockers (L-type and T-type; e.g.diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, and spironolactone), renin inhibitors, ACEinhibitors (e.g., captopril, Vanlev®, pravachol, zofenopril, fosinopril,enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril,ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan,irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan,atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidaseinhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat andgemopatrilat), nitrates, and cardiac glycosides (e.g., digitalis andouabain).

[0170] Examples of suitable cholesterol/lipid lowering agents for use incombination with the compounds of the present invention include HMG-CoAreductase inhibitors, squalene synthetase inhibitors, fibrates, bileacid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenaseinhibitors, an ileal Na⁺/bile acid cotransporter inhibitor, cholesterolabsorption inhibitors, and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

[0171] In addition, the compounds may be used with other agents toincrease the levels of cAMP or cGMP in cells for a therapeutic benefit.For example, applicants have discovered that MC-1R agonists includingthe compounds of the invention have advantageous effects when used incombination with phosphodiesterase inhibitors, including PDE1 inhibitors(such as those described in Journal of Medicinal Chemistry, Vol. 40, pp.2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (such as revizinone,pimobendan, or olprinone), PDE4 inhibitors (such as rolipram,cilomilast, or piclamilast), and PDE7 inhibitors. The compounds of thisinvention also may be used in combination with PDE5 inhibitors such assildenafil, sildenafil citrate, (e.g., when treating sexual dysfunction)or IC-351.

[0172] The combination of the inventive compounds with other therapeuticagents may prove to have additive and synergistic effects. Thecombination may be advantageous to increase the efficacy of theadministration or decrease the dosage to reduce possible side-effects.

[0173] The compounds of formula I may be administered by any meanssuitable for the condition to be treated. The compounds may be deliveredorally such as in the form of tablets, capsules, granules, powders, orwith liquid formulations including syrups; sublingually; bucally;transdermally; parenterally such as by subcutaneous, intravenous,intramuscular, or intrasternal injection or infusion (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; rectally such as in the form ofsuppositories; or liposomally. Dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents may beadministered. The compounds may be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved with suitable pharmaceutical compositions or,particularly in the case of extended release, with devices such assubcutaneous implants or osmotic pumps.

[0174] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The inventive compounds maybe orally delivered by sublingual and/or buccal administration, e.g.,with molded, compressed, or freeze-dried tablets. Exemplary compositionsmay include fast-dissolving diluents such as mannitol, lactose, sucrose,and/or cyclodextrins. Also included in such formulations may be highmolecular weight excipients such as celluloses (AVICEL®) or polyethyleneglycols (PEG); an excipient to aid mucosal adhesion such ashydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer(e.g., GANTREZ®); and agents to control release such as polyacryliccopolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloringagents and stabilizers may also be added for ease of fabrication anduse.

[0175] Exemplary compositions for nasal aerosol or inhalationadministration include solutions which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhanceabsorption and/or bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0176] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides and fattyacids, including oleic acid.

[0177] Exemplary compositions for rectal administration includesuppositories which may contain, for example, suitable non-irritatingexcipients, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures butliquefy and/or dissolve in the rectal cavity to release the drug.

[0178] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art. The specific doselevel and frequency of dosage for any particular subject may vary andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.An exemplary effective amount of compounds of formula I may be withinthe dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (orfrom about 1 to about 2500 mg, preferably from about 5 to about 2000 mg)on a regimen in single or 2 to 4 divided daily doses. Preferred subjectsfor treatment include animals, most preferably mammalian species such ashumans, and domestic animals such as dogs, cats, horses, and the like,subject to melanocortin-receptor associated conditions.

[0179] Each of the inventive compounds exemplified herein has beentested and shown activity at a measurable level for modulating amelanocortin receptor, according to an assay described below and/or anassay known in the field, such as, for example, assays described in WO00/74679 A1 and WO 01/91752.

[0180] Assays

[0181] MC1R

[0182] HBL cells, a human melanoma cell line licensed from Prof. G.Ghanem (Lab. of Oncology & Exp. Surgery, Free University of Brussels,Brussels, Belgium) were used as a source of the human MC-1R. cAMP wasmeasured using the cAMP SPA Direct Screening Assay System from Amersham(RPA 559). 20,000 HBL cells were plated into each well of a half-area 96well white plate and were used between 16-48 hours after plating. Cellswere incubated at 37° C. for 15 minutes in 25 uM IBMX to inhibitphosphodiesterase activity. As per kit instructions, Assay BufferConcentrate was diluted 1 to 50 with dH₂O to prepare Assay Buffer (50 mMacetate buffer containing 0.01% sodium azide). Vials containing rabbitanti-succinyl cAMP serum and the tracer, adenosine 3′,5′-cyclicphosphoric acid 2′-0-succinyl-3-[¹²⁵I] iodotyrosine methyl ester, wereresuspended with 7.5 ml Assay Buffer. SPA anti-rabbit reagent (donkeyanti-rabbit IgG coupled to SPA PVT beads) was resuspended with 15 mlAssay Buffer. All reagents were stored at 4° C. after reconstitution.Melanocortin ligands or compounds were prepared in DMSO and added to theIBMX-treated cells as 100× concentrated stocks. 50 nM α-MSH was used forthe maximum response and 1 ul DMSO was included in the negative controlwells. The final concentration of DMSO was 1% in all the samples. After15-30 minutes of stimulation, the reaction was terminated by theaspiration of the contents of the well followed by addition of 15 ulAssay Buffer containing 0.1 N HCl. Plates were kept at room temperaturefor at least 30 minutes to effect extraction of cAMP. Antiserum, Tracer,and SPA anti-rabbit reagent solutions were mixed 1:1:1 just prior touse. 15 ul of SPA reagent mixture was dispensed into each well andplates were incubated at room temperature for a minimum of 5 hours.Plates were subsequently counted for 6 minutes per sample in a TopCountscintillation reader with background subtraction. Data was analyzed inrelation to a cAMP standard curve.

[0183] MC-4R

[0184] A. Binding Assay.

[0185] The membrane binding assay may be used to identify competitiveinhibitors of [¹²⁵I]NDP-α-MSH binding to cloned human MC4R expressed inHi5 insect cells infected by a baculovirus/human MC4R receptorconstruct.

[0186] Hi5 cells are grown in suspension in Express Five SFM Insect CellMedia (Gibco, Cat. No. 10486-025) at 27° C. with constant shaking. Hi5cells are infected using the following protocol:

[0187] Cells at a density of 1×10⁶ cells/mL are spun down at 1000 rpm(Beckman GS-6KR centrifuge) for 10 minutes.

[0188] Cells are resuspended in 10% of their original volume in asterile 50 mL conical centrifuge tube wrapped with aluminum foil. Virusis added at a Multiplicity of Infection (MOI) of 3 and incubated for 1hour at room temperature with gentle shaking.

[0189] This cell/virus mix is added to the appropriate volume of mediumto attain the original volume and incubated at 27° C. with constantshaking for 72 hours.

[0190] Cells are spun down in 50 mL conical centrifuge tubes at 1000 rpmfor 10 minutes. Each of the resulting pellets are resuspended in 10 mLof cold (4° C.) membrane buffer (25 mM HEPES, pH 7.4, 140 mM NaCl, 1.2mM MgCl₂, 2.5 mM CaCl₂, 10 μG/mL Aprotinin, 10 gG/mL Leupeptin) andDounce homogenized using 10-12 strokes. Dilute to 30 mL with buffer andcentrifuge at 18,000 rpm, 4° C., 15 minutes (Sorvall RC5C Centrifuge).The resulting pellet is resuspended in cold membrane buffer in a totalof ¼ of the original volume by vortexing and aspiration using a syringeand 27 gauge needle.

[0191] Protein content is determined (Bradford, Bio-Rad Protein Assay).Membranes are aliquoted in microcentrifuge tubes and quick frozen inliquid nitrogen. Store at −80° C. until use.

[0192] The membrane binding buffer is composed of 25 mM HEPES, pH 7.4,140 mM NaCl, 1.2 mM MgCl₂, 2.5 mM CaCl₂, 0.1% BSA. 160 μL of membranebinding buffer containing 0.5 μg membrane protein is added to 20 μL of1.0 nM [1²⁵]-NDP-α-MSH (final concentration is 0.1 nM) and 20 μL ofcompeting drug or buffer and incubated for 90 minutes at 37° C.

[0193] The mixture is filtered with Brandel Microplate 96 filterapparatus using 96-well GF/B filter presoaked in 1-% polyethyleneimine(Sigma). The filter is washed (4 times with a total of 1 mL per well)with cold wash buffer consisting of 20 mM HEPES, pH 7.4, 5 mM MgCl₂.

[0194] The filter is dried and punched into a 96 well sample plate(Wallac, 1450-401). 100 μl of Wallac Optiphase Supermix scintillationfluid is added to each well. The top is sealed and the plates are shakento insure that the filters are thoroughly soaked with fluid. Plates arethen counted in a Wallac Microbeta Trilux Scintillation and LuminescenceCounter (Model 1450). Dose-response curves are fitted by linearregression analyses and IC₅₀ values are calculated using ExcelFit.

[0195] B. Functional assay.

[0196] Functional membrane based [³⁵S]GTPγS binding assays are developedto discriminate agonists and antagonists.

[0197] Membrane preparation. Cells (HEK-293 cells expressing the humanMC4R) are grown in Minimum Essential Medium with Earle's salts andL-glutamate (Life Technologies, Cat. # 11095-080) containing 10%heat-inactivated fetal bovine serum, 400 μg/mL geneticin and 100 mMsodium pyruvate in T175 flasks. Upon reaching confluence, cells aredissociated from tissue culture flasks by rinsing with Ca²⁺ and Mg²⁺free phosphate buffered saline (Life Technologies, Cat. # 14190-144) anddetached following 5 minutes incubation at 37° C. with enzyme free celldissociation buffer (Life Technologies, Cat. # 13151-014). Cells arecollected by centrifugation and resuspended in membrane preparationbuffer consisting of 20 mM HEPES, pH 7.4, 10 mM EDTA, 10 gg/mL aprotininand 10 gg/mL leupeptin. The suspension is homogenized by polytron PT3000for 30 sec at 20,000 rpm, and centrifuged at 35,000×g for 15 minutes at4° C. The pellet is resuspended in membrane preparation buffer and thelast centrifugation is repeated. The final pellet is resuspended inmembrane storage buffer consisting of 20 mM HEPES, pH 7.4, 0.1 mM EDTA,10 μg/mL aprotinin and 10 μg/mL leupeptin. Protein concentration isdetermined by the Bio-Rad method (Bio-Rad, Cat.# 500-0006) and thepreparation is diluted to a final protein concentration of 1 mg/mL.Aliquots are stored at −70° C. until used.

[0198] [³⁵S]GTPγS membrane binding assay. Compounds are dissolved at 10mM concentration in DMSO and diluted to the requited concentration intoassay buffer. GTPγS to determine nonspecific binding is prepared at 100μM concentration in assay buffer. The final concentration of DMSO in theassay is 1%. The assay buffer is consisting of 20 mM HEPES, pH 7.4, 100mM NaCl₂, 5 mM MgCl₂, 0.5 μM GDP, 10 gg/mL saponin, 10 μg/mL aprotininand 10 μg/mL leupeptin. The assay is composed by adding 50 μL 10× drugsolution, 200 μL membrane preparation (containing 2-4 μg protein), 50 μL[³⁵S]GTPγS (100,000-150,000 CPM) and 200 μL assay buffer to achieve atotal volume of 500 μL. The assay mixture is incubated at roomtemperature for exactly 30 minutes. The reaction is terminated by rapidfiltration under vacuum through Whatman GF/B filters using a Brandel 96wells cell harvester, followed by washing four times with cold washbuffer consisting of 20 mM HEPES, pH 7.4, and 5 mM MgCl₂. The filtersare air-dried and 200 μL Wallac, Optiphase Super Mix, liquidscintillation cocktail is added to each filter. The bound radioactivity(CPM) is determined by Wallac Trilux 1450 MicroBeta liquid scintillationand Luminescence counter after six hours.

[0199] Data interpretation. NDP-α-MSH is used as reference compound andits maximal stimulation is measured at 1 μM (Ref CPM 100%). Totaldrug-independent binding (Total CPM) is measured in the absence ofcompounds. Response triggered by compounds is expressed as percentNDP-α-MSH response. Compound dose response curves are generated by ExcelXL Fit. The top of the curve represents the compound's intrinsicactivity expressed as % of maximal stimulation.

[0200] C. Radioligand binding assays.

[0201] Binding of [¹²⁵I]-(Nle⁴, D-Phe⁷)-α-MSH to human melanocortinreceptors was performed using membrane homogenates from Hi5 cells thatexpress recombinant MC4 receptors (Hi5-MC4 cells) and from HEK-293 cellsthat express recombinant MC3 receptors (HEK-MC3 cells) or MC5 receptors(HEK-MC5 cells) as well as from HBL cells expressing the human MC1Rreceptor. Homogenates (˜0.5 μg protein/well) were incubated with[¹²⁵I]-(Nle⁴,D-Phe⁷)-α-MSH (100 pM for assays with MC4 receptors and 50pM for assays with MC3/5 receptors) and increasing concentrations ofcompetitors (final concentration of DMSO ═1%) for 90 min at 37° C. inbuffer consisting of 25 mM HEPES (pH 7.4), 140 mM NaCl₂, 2.5 mM CaCl₂,1.2 mM MgCl₂ and 0.1% BSA (10 μg/ml aprotinin and 10 μg/ml leupeptinwere added to assays with MC3/5 receptors). Assays were stopped byaddition of cold wash buffer (20 mM HEPES and 5 mM MgCl₂ for assays withMC4 receptors and 20 mM HEPES for assays with MC3/5 receptors).Filtration over glass fiber filters (Whatman GF/B previously soaked in1% PEI for assays with MC4 receptors or 0.5% PEI for assays with MC3/5receptors) was performed using a Brandel cell harvester. Non-specificbinding was defined with 1 μLM NDP-α-MSH.

[0202] The following Examples illustrate embodiments of the inventivecompounds and starting materials, and are not intended to limit thescope of the claims. For ease of reference, the following abbreviationsare used herein:

Abbreviations

[0203] Boc=tert-butoxycarbonyl

[0204] CBZ=benzyloxycarbonyl

[0205] DEA=diethylamine

[0206] DMAP=4-dimethylaminopyridine

[0207] DMF=N,N-dimethylformarnide

[0208] DMSO=dimethylsulfoxide

[0209] EDC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride

[0210] Et=ethyl

[0211] EtOH=ethanol

[0212] EtOAc=ethyl acetate

[0213] FMOC=fluorenylmethoxycarbonyl

[0214] HOBT=1-hydroxybenzotriazole hydrate

[0215] NMM=N-methylmorpholine

[0216] Me=methyl

[0217] MeOH=methanol

[0218] mp=melting point

[0219] Ph=phenyl

[0220] THF=tetrahydrofuran

[0221] TFA=trifluoroacetic acid

[0222] tlc=thin layer chromatography

[0223] RT=room temperature

[0224] h=hours

[0225] HCl=hydrogen chloride

[0226] mmol=millimole

[0227] Et₃N=triethylamine

[0228] EtOAc=ethyl acetate

[0229] Et₂O=diethyl ether

[0230] Na₂SO₄=sodium sulfate

[0231] NaOH=sodium hydroxide

[0232] LiOH=lithium hydroxide

[0233] CH₂Cl₂=methylene chloride

[0234] HPLC=high pressure liquid chromatography

[0235] LRMS=low resolution mass spectrometry

[0236] In the examples, when a letter is used in a superscript followingthe data, such as 3.28^(a), the letter denotes the conditions used forthe HLPC/MS, as follows:

[0237] Method A: Column Primesphere C18-HC 4.6×30 mm, gradient time: 2minutes, Hold time: 1 minutes, Flow rate: 4 mL/min, Detector Wavelength:220 nM, Solvent A=10 % AcCN/90% H₂O/5mM NH₄OAc, Solvent B=90% AcCN/10%H₂O/5mM NH4OAc, Start % B=0/ Finish % B=100;

[0238] Method B: Column Primesphere C18-HC 4.6×30 mm, gradient time: 2minutes, Hold time: 1 minutes, Flow rate: 4 mL/min, Detector Wavelength:220 nM, Solvent A: 10 % AcCN/90% H₂O/0.1% TFA, Solvent B: 90% AcCN/10%H₂O/0.1% TFA, Start % B=0/Finish % B=100;

[0239] Method C: Column Primesphere C18-HC 4.6×30 mm, gradient time: 3minutes, Hold time: 1 minutes, Flow rate: 4 mL/min, Detector Wavelength:220 nM, Solvent A: 10% AcCN/90% H₂O/0.1% TFA, Solvent B: 90% AcCN/ 10%H₂O/0.1% TFA, Start % B=0/ Finish % B=100.

EXAMPLE 1

[0240]

[0241] Step A:

[0242] To a solution of N-Boc-D-4-methyltyrosine

[0243] (4.9 g, 16.5 mmol), EDC (4.3 g, 22.5 mmol), HOBT (3.0 g, 22.5mmol), DMAP (0.2 g, 0. 15 mmol) in CH₂Cl₂, and s DMF (1:1, 50 mL) wereadded Et₃N (10.5 mL, 75.0 mmol) and 4-butanoyl-4-phenyl-piperdinehydrogen chloride

[0244] (4.0 g, 15.0 mmol), sequentially. The reaction mixture wasstirred at RT overnight. The reaction mixture was diluted with EtOAc(200 mL) and washed with HCl (1 N, 200 mL), water (200 mL), NaOH (0.5 N,200 mL), and water (200 mL). The organic layer was dried over anhydrousNa₂SO₄, and the solvent was subsequently removed under reduced pressure.The resulting material was>90% pure as judged by HPLC and used withoutfurther purification.

[0245] Step B:

[0246] To a solution of compound 1A (12.0 mmol) in wet CH₂Cl₂ (30 mLplus 2 mL water) was added TFA (15 mL). The solution was stirred at RTfor 1 h before removing the solvents. The residue was dissolved in EtOAc(300 mL) and washed with water (200 mL), NaOH (0.5 N, 200 mL), and water(200 μL). The organic layer was dried over 5 anhydrous Na₂SO₄, and thesolvent removed under reduced pressure. The resulting material (compound1B) was>90% pure as judged by HPLC and used without furtherpurification.

[0247] Step C:

[0248] To a solution of Nα-Fmoc-3-(4-N-Boc-piperidine)-L-alanine (0.33g, 0.67 mmol), EDC (0.18 g, 0.92 mmol), HOBT (0.09 g, 0.92 mmol), DMAP(catalytic) in CH₂Cl₂, and DMF (1:1, 50 mL) were added Et₃N (0.25 μL,1.8 mmol) and compound 1B (0.25 g, 0.61 mmol), sequentially. Thereaction mixture was stirred at RT overnight. The reaction mixture wasdiluted with EtOAc (200 mL) and washed with HCl (1 N, 200 mL), water(200 mL), NaOH (0.5 N, 200 mL), and water (200 mL). The organic layerwas dried over anhydrous Na₂SO₄, and the solvent was subsequentlyremoved under reduced pressure to provide compound 1C.

[0249] Step D:

[0250] Compound 1C was treated with diethylamine in CH₂Cl₂ (20%)followed by evaporation, to provide compound 1D.

[0251] Step E:

[0252] Compound 1D was treated with TFA as described in Step B. Example1 was obtained which was purified by preparative HPLC with a purity of89% as judged by HPLC.

EXAMPLE 2

[0253]

[0254] Step A:

[0255] To a solution of N-Boc-L-histidine

[0256] (3.1 g, 12.7 mmols), EDC (3.6 g, 19.1 mmols), HOBT (2.6 g, 19.1mmols), DMAP (0.16 g, 1.3 mmols) in CH₂Cl₂, and DMF (1:1, 50 mL) wereadded Et₃N (8.8 mL, 64.0 mmols) and D-4-methoxyphenylalanine methylester hydrochloride

[0257] HCl](2.9 g, 12.0 mmol), sequentially. The reaction mixture wasstirred at RT overnight. The reaction mixture was diluted with EtOAc(200 mL) and washed with water (200 mL), NaOH (0.5 N, 200 mL), and water(200 mL). The organic layer was dried over anhydrous Na₂SO₄, and thesolvent was subsequently removed under reduced pressure. The resultingcompound 1A was>90% pure as judged by HPLC and used without furtherpurification in Step B.

[0258] Step B:

[0259] To a solution of Compound 2A (12.0 mmol) in CH₃OH (13 mL) wasadded NaOH (2N, 13 mL) to make the final concentration of NaOH ˜1 N.This solution was stirred at RT for 2 h before being diluted with water(100 mL). The aqueous layer was extracted with Et₂O (100 mL×2), and theorganic matter was discarded. The aqueous layer was acidified with HCl(6 N) to pH ˜2, and extracted with EtOAc (100 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, and the solvent wassubsequently removed under reduced pressure. The resulting Compound 2Bwas a white solid with a purity>90% as judged by HPLC. This intermediatewas used without further purification for Step C.

[0260] Step C:

[0261] To a solution of Compound 2B (0.5 g, 1.1 mmols), EDC (0.3 g g,1.6 mmols), HOBT (0.22 g, 1.6 mmols), and DMAP (0.13 g, 1.1 mmols) inCH₂Cl₂ (25 mL) were added Et₃N (0.8 mL, 5.5 mmols) and4-butyryl-4-phenyl-piperidine hydrochloride (0.35 g, 1.3 mmols),sequentially. The reaction mixture was stirred at RT overnight. Thereaction mixture was diluted with EtOAc (100 mL) and washed with HCl(0.5 N, 100 mL), water (100 mL), NaOH (0.5 N, 100 mL), and water (100mL). The organic layer was dried over anhydrous Na₂SO₄, and the solventremoved under reduced pressure. The resulting Compound 1C was >90% pureas judged by HPLC and used without further purification in Step D.

[0262] Step D:

[0263] To a solution of the Boc-protected Compound 2C (1.1 mmols) in wetCH₂Cl₂ (20 mL plus 1 mL water) was added TFA (10 mL). The solution wasstirred at RT for 1 h before the solvents were removed. The crudereaction mixture was purified by preparative HPLC to obtain compound 2Dat>95% purity as judged by HPLC. HPLC (min)=2.5, MS (M+H)⁺=546.4.

[0264] Step E:

[0265] To a solution of compound 2D (0.1 g, 0.18 mmol) in CH₂Cl₂ (10 mL)was added Et₃N (0.075 mL, 0.54 mmol). This solution was cooled to 0° C.,and then acetyl chloride was added (0.02 g, 0.27 mmol). The reactionmixture was stirred at RT until all the amine was consumed. The reactionmixture was diluted with EtOAc (100 μL) and washed with HCl (0.5 N, 100mL), water (100 μL), NaOH (0.5 N, 100 mL), and water (100 mL). Theorganic layer was dried over anhydrous Na₂SO₄, and the solvent removedunder reduced pressure to provide Example 2 which was purified bypreparative HPLC. Purity=94%, HPLC ret. time (min.)=2.71, MS (M+H)⁺=588.

EXAMPLES 3-43

[0266]

[0267] Compounds of the above formulae (A) and (B), wherein the groups Gand x have the values listed in Table 1, were prepared following theprocedure described above for Example 2: TABLE 1 HPLC Purity RT Mass Ex.Core x G (%) (min) (M + H)  3 B 0

87 2.6 537.21  4 B 0

80 3.6 586.5  5 A 0

83 3.7 602.46  6 A 0

78 3.4 540.43  7 A 0

85 3.1 586.23  8 B 0

93 3.0 505.35  9 B 1

85 2.7 524.22 10 B 2

84 2.7 538.24 11 B 2

100  2.7 537.28 12 B 0

92 2.6 523.17 13 A 0

93 2.6 523.35 14 A 0

78 3.1 632.18 15 A 0

83 3.3 620.37 16 A 0

95 3.1 600.24 17 A 0

94 2.8 526.05 18 A 0

78 3.2 620.26 19 A 0

96 2.7 538.23 20 A 2

81 2.7 538.14 21 A 0

91 2.5 549 22 B 0

86 2.56 549.31 23 A 0

88 2.49 549.3 24 B 0

91 2.52 549.31 25 B 0

89 2.53 563.42 26 A 0

78 2.62 566.29 27 B 0

83 2.67 566.31 28 B 0

87 2.6 537.21 29 B 0

80 3.6 586.5 30 A 0

83 3.7 602.46 31 A 0

78 3.4 540.43 32 A 0

85 3.1 586.23 33 B 0

93 3.0 505.35 34 B 0

92 2.6 523.17 35 A 0

93 2.6 523.35 36 A 0

78 3.1 632.18 37 A 0

83 3.3 620.37 38 A 0

95 3.1 600.24 39 A 0

94 2.8 526.05 40 A 0

78 3.2 620.26 41 A 0

96 2.7 538.23 42 A 0

78 2.62 566.29 43 B 0

83 2.67 566.31

EXAMPLES 44-48

[0268]

[0269] Compounds having the above formula (Ig), wherein W, y and R₁₅have the values Table 2, were prepared following the same or similarprocedure as described or Example 2. TABLE 2 Purity HPLC Ret MS Ex. W yR₁₉ R₃₀ (%) time (min) (M + H) 44

1 —CH₃ —OCH₃ 94 2.71 588 45

1

—OCH₃ 96 2.97 650.27 46

1 —CH₃ Cl 96 — 593 47

1

Cl 90 — 655 48 NH₂ 3 —CH₃ —OCH₃ 80 2.67 565.29

EXAMPLES 49-84

[0270]

[0271] Compounds of formula (Ih), above, wherein R₂ has the valueslisted in Table 3, were prepared following the same or similar procedureas described above for Example 2. TABLE 3 HPLC Ex. Purity RT Mass No. R₂(%) (min) (M + H) 49

79 3.2 524.39 50

84 3.3 524.39 51

80 3.2 564.28 52

81 3.1 603.34 53

93 3.5 608.37 54

84 3.4 572.34 55

86 3.5 608.37 56

85 3.3 576.31 57

96 3.5 684.22 58

72 3.5 614.34 59

88 3.6 564.37 60

85 3.6 626.27 61

92 3.7 634.38 62

91 3.5 634.38 63

71 3.4 662.34 64

92 3.5 636.26 65

87 3.4 584.35 66

84 3.3 536.38 67

86 3.4 592.32 68

84 3.3 594.33 69

83 3.3 576.31 70

84 3.3 576.31 71

80 3.4 594.31 72

89 3.4 592.31 73

78 3.5 614.39 74

83 2.5 559.32 75

82 2.9 565.27 76

82 2.5 559.31 77

79 3.0 583.32 78 H 81 2.7 468.29 79 —CH₃ 84 2.8 482.31 80

85 3.0 583.33 81

80 3.4 572.33 82

75 3.4 584.33 83

88 3.0 618.37 84

86 3.8 578.38

EXAMPLES 85-93

[0272]

[0273] Compounds of formula (Ii), above, wherein A has the values listedin Table 4, were following the same or similar procedure as describedabove for Example 2. TABLE 4 HPLC Ex. Purity ret. t. = Mass No. A (%)(min) (M + H) 85 —CH₂CH₂— 76 2.7 482.32 86

71 3.2 570.32 87

80 3.1 530.32 88

73 3.0 522.38 89

87 2.9 522.38 90

76 3.3 586.36 91

80 3.2 584.34 92

71 3.4 584.33 93

83 3.4 584.35

EXAMPLES 94-145

[0274]

[0275] Compounds having the above formula (Ij), wherein R₁₉ has thevalues listed in Table 5, were prepared following the same or similarprocedure as described above for Examples 1 and 2. TABLE 5 HPLC Ex.Purity RT Mass No. R₁₉ (%) (min) (M + H)  94

84 3.59 729.4  95

90 2.84 695.9  96

80 3.72 743  97

88 3.43 710.9  98

81 3.37 680.9  99

80 3.21 690.9 100

82 3.43 696.9 101

84 3.53 701.3 102

85 3.02 667.9 103

84 2.97 667.9 104

85 3.49 710.9 105

85 3.41 711.9 106

81 3.7 743 107

76 3.46 724.9 108

85 3.61 729.4 109

75 3.58 708.9 110

75 3.61 686.9 111

80 3.27 717.9 112

80 3.6 759 113

81 3.72 759 114

75 3.52 672.9 115

90 3.08 604.8 116

75 3.73 759 117

75 3.16 618.8 118

85 2.89 656.8 119

75 3.2 630.8 120

75 3.12 709.9 121

80 3.24 632.9 122

90 3.36 646.9 123

78 3.2 656.8 124

90 3.32 684.9 125

73 3.4 684.9 126

79 3.45 694.9 127

75 3.35 701.3 128

80 3.54 701.3 129

75 3.27 704.9 130

81 3.33 710.9 131

75 3.25 711.9 132

88 3.39 711.9 133

84 3.5 716.9 134

80 3.25 632.9 135

80 3.41 684.9 136

77 3.51 724.9 137

80 3.43 724.9 138

75 3.51 672.9 139

80 3.49 692.9 140

75 3.39 696.9 141

90 3.36 646.9 142

90 3.41 658.9 143

90 2.96 709.9 144

80 3.35 696.9 145

90 3.36 696.9

EXAMPLES 146-200

[0276]

[0277] Compounds having the above formula (Ik), wherein R₁₉ has thevalues listed in Table 6, were prepared following the same or similarprocedure as for Example 1. TABLE 6 HPLC Ex. Purity RT Mass No. R₁₉ (%)(min) (M + H) 146

80 3.36 642.4 147

70 3.56 712.3 148

75 3.47 656.4 149

76.5 2.83 679.3 150

75.7 3.69 742.3 151

75.1 3.68 726.4 152

80 3.18 614.4 153

72.6 3.11 693.4 154

75 3.23 616.4 155

80 3.31 630.4 156

72 3.39 694.4 157

75 3.33 630.4 158

90 3.16 640.4 159

85 3.32 664.4 160

80.4 3.28 668.3 161

78.2 3.36 668.3 162

70 3.17 674.4 163

75 3.45 676.4 164

75 3.36 680.3 165

75 3.33 680.3 166

75.3 3.49 684.3 167

76.1 3.5 684.3 168

80 3.01 651.3 169

85 2.96 651.3 170

70 3.24 688.4 171

79.4 3.3 694.3 172

82.9 3.34 695.3 173

83.7 3.37 695.3 174

75 3.66 726.4 175

75 3.31 630.4 176

70 3.21 616.4 177

79.6 3.36 668.3 178

85 3.52 706.3 179

70 3.47 708.4 180

70 3.42 708.4 181

70 3.43 708.4 182

70 3.59 712.4 183

75.5 3.54 692.4 184

75 3.46 656.4 185

72 3.56 670.4 186

72 3.25 701.4 187

76.3 3.68 742.4 188

90 2.95 693.4 189

90 3.32 680.3 190

90 4.33 695.3 191

90 3.57 742.3 192

90 3.13 602.3 193

90 3.29 684.3 194

90 3.44 694.3 195

92 3.45 700.4 196

90 3.26 670.3 197

90 3.53 726.3 198

90 4.33 640.3 199

90 3.33 693.4 200

90 3.37 680.3

EXAMPLES 201-215

[0278]

[0279] Compounds having the above formula (II), wherein J and R₁₉ havethe values listed in Table 7, were prepared following the same orsimilar procedure as for Example 1. For examples 201-205 and 213-215, inthe last step, compound 2D was dissolved in DCM and reacted with 1.2 eqof the appropriate sulfonyl chloride or chloroformate in presence of 3eq of resin bound morpholine (Argonaut Technologies) at RT overnight.After filtration and concentration the residue was purified by RP-prepHPLC. For examples 206-212, in the last step compound 2D was reactedwith 1.1 eq of the appropriate isocyanate in toluene at RT overnight.After concentration, the residue was purified by RP-prep HPLC. TABLE 7HPLC Ex. Purity RT Mass No. J R₁₉ (%) (min) (M + H) 201 —SO₂— —CH₃ 863.03 623.8 202 —SO₂— —CH₂CH₃ 80 3.10 637.8 203 —SO₂— —CH₂CH₂CH₃ 95 3.20651.8 204 —SO₂—

95 3.22 685.8 205 —SO₂—

95 3.32 699.9 206 —C(═O)NH— —CH₂CH₃ 92 3.12 616.8 207 —C(═O)NH— —CH₃ 803.05 602.7 208 —C(═O)NH— —CH(CH₃)(CH₃) 95 3.22 630.8 209 —C(═O)NH——CH₂CH₂CH₃ 95 3.23 630.8 210 —C(═O)NH—

95 3.36 664.8 211 —C(═O)NH—

95 3.46 670.9 212 —C(═O)NH—

95 3.36 678.8 213 —CO₂— —CH₂CH₂CH₃ 94 3.69 631.8 214 —CO₂— —CH₃ 91 3.47603.7 215 —CO₂— —CH₂CH₃ 90 3.56 617.8

EXAMPLE 216

[0280]

[0281] Example 216 was prepared following the same or similar procedureas described above for Example 2. In the last step, 2D was reacted with1.2eq of phenylchloroformate in DCM in presence of 3 eq of resin boundmorpholine. After filtration and concentration, the residue was purifiedby RP-prep HPLC. Purity=98%, HPLC ret. time (min)=3.42, MS (M+H)⁺=572.

EXAMPLES 217-311

[0282]

[0283] Compounds having the above formula (Im), wherein E has the valueslisted in Table 8, were prepared following the same or similar procedureas for Example 1. TABLE 8 HPLC Ex. Purity RT Mass No. E (%) (min) (M +H) 217

88.9% 2.2 427.5 218

87.4% 2.6 573.7 219

74.0% 2.6 587.7 220

92.7% 2.4 441.5 221

78.6% 2.6 533.6 222

80.6% 3.0 517.6 223

85.5% 2.7 455.6 224

96.0% 1.7 524.7 225

88.4% 2.6 455.6 226

80.8% 3.1 495.6 227

92.0% 1.6 510.6 228

80.9% 3.1 601.6 229

85.4% 2.7 588.7 230

86.2% 2.5 575.7 231

88.3% 3.2 531.7 232

86.5% 3.1 547.7 233

85.4% 3.2 618.1 234

87.2% 2.8 613.7 235

92.3% 3.3 565.7 236

85.2% 2.8 489.6 237

85.6% 3.0 517.6 238

93.0% 2.6 572.7 239

89.3% 2.5 558.6 240

81.3% 2.6 572.7 241

80.6% 3.4 567.7 242

84.8% 2.7 587.7 243

87.7% 2.6 572.7 244

93.2% 3.5 601.7 245

86.7% 3.2 541.7 246

84.7% 3.2 625.7 247

89.6% 3.4 587.7 248

84.2% 3.5 523.7 249

90.1% 3.6 615.8 250

80.0% 3.1 483.6 251

86.2% 3.0 584.7 252

82.3% 3.2 497.6 253

71.0% 2.6 587.7 254

91.1% 3.4 557.7 255

82.6% 2.7 577.7 256

81.5% 3.2 575.7 257

80.4% 1.8 521.6 258

79.7% 2.9 589.7 259

93.0% 2.0 574.7 260

91.0% 2.3 589.7 261

93.4% 3.3 579.7 262

79.8% 3.0 554.0 263

71.0% 3.2 547.7 264

77.6% 3.3 556.7 265

85.8% 3.6 607.8 266

95.0% 3.8 617.8 267

91.4% 3.7 619.8 268

84.7% 3.0 588.7 269

92.5% 3.4 559.7 270

82.4% 3.5 533.7 271

86.4% 3.0 547.7 272

94.0% 3.6 607.8 273

75.0% 2.0 574.6 274

82.0% 2.9 588.7 275

88.4% 3.2 604.8 276

86.0% 2.3 427.5 277

88.7% 2.5 441.5 278

88.7% 2.7 455.6 279

88.7% 3.0 469.6 280

74.8% 2.6 507.6 281

88.5% 3.3 485.6 282

81.2% 2.6 443.5 283

86.0% 2.9 457.6 284

90.2% 3.3 567.7 285

80.0% 2.1 415.5 286

79.0% 2.9 491.6 287

86.0% 2.8 489.6 288

90.3% 3.5 511.7 289

88.1% 3.3 509.7 290

78.2% 3.0 505.6 291

89.2% 2.5 534.6 292

80.0% 3.4 543.7 293

85.5% 1.3 456.5 294

87.9% 1.9 532.6 295

78.3% 1.4 527.7 296

94.0% 1.4 484.6 297

86.5% 1.7 510.6 298

95.5% 2.3 562.6 299

75.0% 1.9 573.7 300

87.8% 2.2 588.7 301

84.9% 1.9 524.7 302

75.4% 2.1 526.7 303

91.8% 2.5 595.7 304

78.1% 2.0 607.7 305

90.5% 2.2 590.7 306

91.0% 1.9 588.7 307

83.1% 2.2 538.7 308

88.7% 2.9 559.6 309

89.3% 3.1 634.7 310

90.1% 2.4 588.7 311

88.4% 2.4 622.7

EXAMPLES 312-316

[0284]

[0285] Compounds having the above formulae A or B, wherein G and R₂₂have the values listed in Table 9, were prepared following the same orsimilar procedure as for Example 1. TABLE 9 HPLC Ex. Purity RT Mass No.Core G R₂₂ (%) (min) (M + H) 312 A

82.0% 3.8 644.44 313 A

80.0% 4.1 661.43 314 B

91.0% 3.9 626.42 315 A

89.0% 3.4 600.41 316 B

94.1% 3.8 658.44

EXAMPLE 317

[0286]

[0287] Step A:

[0288] Compound 317A was prepared by coupling of commercially availableN-BOC D-4-chlorophenylalanine and4—Cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidine, followed bydeprotection of the BOC group, as described in WO 00/74679.

[0289] Step B:

[0290] To a solution of the compound 317A and the amino acid having theformula,

[0291] in DCM (12 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (736 mg, 3.8 mmol) and HOBt (518 mg, 3.8 mmol) at RT. Themixture was stirred at RT overnight and a sat'd solution of ammoniumchloride (15 ML) was added. The separated aqueous layer was extractedwith DCM (3×25 mL), and the combined organic layers were dried (MgSO₄anh.), filtered, and evaporated to afford compound 317B which was usedin the next step without purification. HPLC (Column: Combiscreen C8 S-54.6×50 mm; Flow rate: 4 mL min, Solvent system: 0-100% B in 4 min.Solvent A: 10% CH₃CN−90% H₂O−0.1% TFA; Solvent B: 90% CH₃CN−10% H₂O−0.1%TFA; UV: 220 nm): retention time 2.40 min, purity 99.2%; HPLC (Column:Luna CN 4.6×30 mm; Flow rate: 4 mL/min, Solvent system: 0-100% B in 4min. Solvent A: 10% CH₃CN−90% H₂O−5 mM NH₄OAc; Solvent B: 90% CH₃CN−10%H₂O−5 mM NH₄OAc; UV: 220 nm): retention time 3.06 min, purity 100%;HPLC/MS (Column: YMC ODS-A C18 4.6×50 mm; Flow rate: 4 mL/min, Solventsystem: 0-100% B in 2min. Solvent A: 10% CH₃CN−90% H₂O−5 mM NH₄OAc;Solvent B: 90% CH₃CN−10% H₂O−5 mM NH₄OAc; UV: 220 nm; Micromass ZMD2000, ESI): retention time 1.81 min, purity 97.8%, MS pos. m/z 541(M+H)⁺; MS (Finigan TSQ 7000, ESI) m/z 541 (M+H)+; ¹H NMR (400 MHz,CD₃OD) δ ppm (two rotamers; ratio 1.8:1) 8.45 (1H, s, minor rotamer),8.43 (1H, s, major rotamer), 7.99 (1H, s, minor rotamer), 7.94 (1H, s,major rotamer), 7.31 (2H, d, J=8 Hz, major rotamer), 7.28 (2H, d, J=8Hz, minor rotamer), 7.23 (2H, d, J=8 Hz, major rotamer), 7.21 (2H, d,J=8 Hz, minor rotamer), 5.82-5.69 (1H, m), 5.26-5.20 (2H, m), 5.05 (1H,dd, J=6, 12 Hz), 4.26 (2H, s, major rotamer), 4.25 (2H, s, minorrotamer), 3.69-3.58 (1H, m), 3.55-3.43 (2H, m), 3.40-3.32 (1H, m),3.01-2.84 (2H, m), 2.63-2.55 (1H, m), 2.50-2.43 (1H, m), 2.37-2.30 (2H,m), 1.85-1.63 (6H, m), 1.45-0.86 (8H, m). ¹³C NMR (100.61 MHz, CD₃OD) δppm (two rotamers; ratio 1.8:1) 171.7 (s, major rotamer), 171.6 (s,minor rotamer), 171.3 (s), 151.7 (d), 146.4 (d), 136.7 (d, minorrotamer), 136.6 (d, major rotamer), 134.1 (s, major rotamer), 134.0 (d,minor rotamer), 132.8 (s, major rotamer). 132.7 (s, minor rotamer),2×132.3 (d, major rotamer), 2×132.1 (d, minor rotamer), 2×129.8 (d,major rotamer), 2×129.7 (minor rotamer), 121.0 (t), 53.0 (t, minorrotamer), 52.7 (t, major rotamer), 51.6 (d, minor rotamer) 51.4 (d,major rotamer), 43.0 (d), 42.8 (t, minor rotamer), 42.6 (t, majorrotamer), 39.1 (s), 2×38.9 (t, major rotamer), 38.7 (t, major rotamer),38.3 (t, minor rotamer), 38.0 (s, major rotamer), 37.9 (s, minorrotamer), 37.1 (t, minor rotamer), 37.0 (t, major rotamer), 31.2 (t),30.6 (t), 2×28.2 (t), 27.6 (t), 3×27.4 (t); ir (v_(max), KBr) cm⁻¹:3565-2500 (broad), 1683, 1635, 1456, 1203, 1139.

[0292] Step C:

EXAMPLE 317

[0293] To a solution of Compound 317B in DCM (10 mL) was added a 20%(v/v) solution of TFA in DCM (1.6 mL) at RT. The mixture was stirred atRT for 8 h and evaporated under reduced pressure. The residue waspurified using preparative HPLC and after evaporation, the residue waslyophilized to afford Example 317 as the TFA salt. HPLC ret. time(min)=1.54^(b), MS (M+H)⁺=541.

EXAMPLES 318-322

[0294]

[0295] Compounds having the above formulae A or B. wherein G has thevalues listed in Table 10 were prepared following the same or similarprocedure as for Example 1. TABLE 10 HPLC Retention Ex. Time MS Data^(b)No. Core G (min) (M + H)⁺ 318 B

3.20^(c) 617 319 A

3.19^(c) 617 320 A

1.52^(b) 541 321 A CH₃SCH₂CH₂— 1.74^(a) 575 322 B

1.52^(a) 544

EXAMPLES 323-328

[0296]

[0297] Compounds of formula (Im), above, wherein the groups G and W havethe values in Table 11, were prepared following the same or similarprocedure described for Example 1, using a different amino acid in placeof N-Boc-L-histidine in Step TABLE 11 Mass Ex No. G W Purity (%) time(min) (M + H) 323

91 2.5 549 324

86 2.56 549.31 325

88 2.49 549.3 326

91 2.52 549.31 327

89 2.53 563.42 328

92 2.58 577.38

1. A compound of formula (I),

or a pharmaceutically-acceptable salt or hydrate, thereof, in which: R₁is hydrogen or C₁₋₆alkyl or is taken together with R₂ or R₃ to form amonocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle; R₂is C₁₋₆alkyl or C₂₋₆alkenyl optionally substituted with one to threearyl, cycloalkyl, or heteroaryl; provided that where G is C₂₋₆alkenyl,A₁—NR₁₈COR₂R₁₉, or A₁—SO₂R₁₇, or when y is 0, R₂, may be or C₁₋₆alkyl orC₂₋₆alkenyl, each optionally substituted with heteroaryl,

G is selected from, A₃-aryl, —OR₁₈, heteroaryl, A₁-cyano, A₂—OR₁₇,A₁—C(═O)R₁₈, A₁—CO₂R₁₈, A₁—C(═O)NR₁₈R₁₉, A₁—OC(═O)R₁₈, A₁—NR₁₈C(═O)R₁₉,A₁—OC(═O)NR₁₈R₁₉, A₁—NR₁₈SO₂R₁₇, A₁—NR₂OC(═O)NR₁₈R₁₉, and A₁—SR₁₈; orwhen y is 0, or when W is a group other than NHR₂₂, G may beA₁-heterocyclo, wherein A₁ is a bond, C₁₋₆alkylene or C₂₋₆alkenylene(straight or branched chain), A₂ is C₁₋₆alkylene or C₂₋₆alkenylene, andA₃ is C₂-6alkenylene; or where G is C₁₋₆alkenyl. A1-NR₁₈CO₂R₁₉, orA₁—SO₂R₁₇, or when y is 0, R₂ may be C₁₋₆alkyl or C₁₋₆alkenyl, eachsubstituted with heteroaryl; W is selected from —NR₂₁R₂₂, —OR₂₃,—NR₂₁C(═O)R₂₄, —NR₂₁CO₂R₂₄, amidino, guanidino, or a substituted orunsubstituted heterocyclo, heteroaryl, or cycloalkyl selected fromazepinyl, azetidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl,pyrazinyl, pyridazinyl, 1,2-dihydropyridazinyl, pyranyl,tetrahydropyranyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolidinyl,piperidinyl, thiazolyl, tetrahydrothiazolyl, thienyl, furyl,tetrahydrofuryl, morpholinyl, isoquinolinyl, tetrahydroisoquinolinyl,tetrazolyl, oxazolyl, tetrahydro-oxazolyl, and C₃₋₇cycloalkyl, whereinsaid heteroaryl, heterocyclo or cycloalkyl groups may additionally havejoined thereto an optionally substituted five-to-seven memberedheterocyclic, heteroaryl, or carbocyclic ring; R₄ and R₇ areindependently selected from hydrogen, alkyl, substituted alkyl, halogen,hydroxy, alkoxy, and keto; R₅, R_(5a), R_(5b), R₆, R_(6a), R_(6b), R₈and R₉ are independently hydrogen, halogen, cyano, alkyl, substitutedalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,—OR₂₅, —NR₂₅R₂₆, —SR₂₅ —S(O)_(p)R₂₆, —C(═O)R₂₅, —OC(═O)R₂₅, —CO₂R₂₅,—C(═O)NR₂₅R₂₆, —NR₂₅C(═O)R₂₆, —OC(═O)NR₂₅R₂₆, —NR₂₅CO₂R₂₆,—NR₂₇C(═O)NR₂₅R₂₆ or —NR₂₅SO₂R₂₆; or R_(5a) and R_(5b), R_(6a) andR_(6b), or R₈ and R₉ taken together form a keto group (═O) or amonocyclic or bicyclic cycloalkyl or heterocyclo,joined in a spirofashion to ring E, or alternatively, R_(5a) and/or R_(5b) together withR₈ and/or R₉, or R_(6a) and/or R_(6b) together with R₈ and/or R₉, aretaken to form a fused carbocyclic, heterocyclic, or heteroaryl ring;provided that, when G is a C₁₋₆alkyl substituted with —OR₁₇, —CO₂R₁₈, or—C(═O)NR₁₈R₁₉, then R_(5a), R_(5b), R_(6a), and R_(6b) are hydrogenprovided R₈ and R₉ are not both hydrogen; R₁₀ is selected from hydrogen,alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, andhetereocyclo; R₁₁ is hydrogen or C₁₋₈alkyl; R₁₂ is C₁₋₈alkyl,substituted C₁₋₈alkyl, or cycloalkyl; R₁₃, R₁₄, R₁₅ and R₁₆ are selectedindependently of each other from hydrogen, alkyl, substituted alkyl,amino, alkylamino, hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, orheterocyclo, or R₁₃ and R₁₄, or R₁₅ and R₁₆, when attached to the samecarbon atom, may join to form a spirocycloalkyl ring; R₁₇ is alkyl,substituted alkyl, cycloalkyl, aryl, heterocyclo, or heteroaryl; R₁₈,R₁₉, and R₂₀ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,cycloalkyl, heterocyclo, or C(═O)R₂₈; or when G is NH(C═O)R₁₉, R₁₉ maybe a bond joined to W to define a heterocyclo ring; provided, however,that when y is at least one, W is imidazolyl, indolyl, —NR₂₁R₂₂, or—OR₂₃, and G is —NR₁₈C(═O)R₁₉, then R₁₉ is not a C₁-alkyl having thesubstituent —NR₂₉R₃₁; R₂₁ and R₂₂ are selected from hydrogen, alkyl, andsubstituted alkyl; R₂₃ and R₂₄ are independently hydrogen, alkyl,substituted alkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl; R₂₅,R₂₆ and R₂₇ are independently hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heterocyclo, or heteroaryl; or R₂₅ and R₂₆ may jointogether to form a heterocyclo or heteroaryl, except R₂₆ is not hydrogenwhen joined to a sulfonyl group as in —S(O)_(p)R₂₆ or —NR₂₅SO₂R₂₆; R₂₈is hydrogen, alkyl, or substituted alkyl; R₂₉ and R₃₁ are selected fromhydrogen, alkyl, haloalkyl, hydroxyalkyl, phenylalkyl, andalkoxycarbonylalkyl, or R₂₉ and R₃₁ taken together form a heterocycloring; n is 0, 1, 2, 3 or 4; p is 1, 2, or 3; x is 0, 1, or 2; y is 0, 1,2, 3 or 4; and z is 0, 1, or
 2. 2. A compound according to claim 1, or apharmaceutically-acceptable salt or hydrate, thereof, in which: ,inwhich: G is selected from: a) —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, and—SO₂R₁₇, b) C₁₋₆alkylene or C₂₋₆alkenylene joined to one of cyano,—OR₁₇, —C(═O)R₁₈, —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, —NR₁₈CO₂R₁₉,—NR₁₈SO₂R₁₇, —SO₂R₁₇, —NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈; c) or when W is agroup other than NHR₂₂, G also may be selected from optionallysubstituted pyrrolidinyl or piperidinyl; R₁₇ is C₁₋₄alkyl,C₅₋₆cycloalkyl, phenyl or benzyl; R₁₈, R₁₉, and R₂₀ are independentlyselected from hydrogen, C₁₋₄alkyl, phenyl, benzyl, C₅₋₆cycloalkyl,—C(═O)CH₂(phenyloxy), —C(═O)CH₂(benzyloxy), inimidazolyl, pyridyl,furyl, thienyl, or C₁₋₄alkyl or C₂₋₄alkenyl substituted with one ofphenyl, pyridyl, furyl, cyclopentyl, cyclohexyl, CO₂Me, phenyloxy, orbenzyloxy, wherein each ringed group of R₁₈, R₁₉, and R₂₀ in turn isoptionally substituted with one to two R₃₆, and/or optionally has abenzene ring or five membered heterocyclo having two oxygen atoms fusedthereto; and R₃₆ is halogen, methoxy, nitro, phenyl, phenyloxy, oralkylamino.
 3. A compound according to claim 2, or apharmaceutically-acceptable salt or hydrate, thereof, in which G is—NR₁₈C(═O)R₁₉, R₁₈ is hydrogen or lower alkyl, and R₁₉ is C₁₋₄alkyl,C₂₋₄alkenyl, phenyl, benzyl, C₅₋₆cycloalkyl, —C(═O)CH₂(phenyloxy),—C(═O)CH₂(benzyloxy), imidazolyl, pyridyl, furyl, thienyl, or C₁₋₄alkylor C₂₋₄alkenyl substituted with one of phenyl, phenyl, pyridyl, furyl,cyclopentyl, cyclohexyl, CO₂Me, phenyloxy, and benzyloxy, wherein eachringed group of R₁₉ in turn is optionally substituted with one to twoR₃₆, and/or optionally has a benzene ring or five membered heterocyclohaving two oxygen atoms fused thereto.
 4. A compound according to claim2, or a pharmaceutically-acceptable salt or hydrate, thereof, in which Wis OH, —NH₂, —NHalkyl, —N(alkyl)₂, azetidinyl, imidazolyl, piperidinyl,pyrrolidinyl, or NHCO₂(alkyl); or a C₄₋₇cycloalkyl optionallysubstituted with lower alkyl, —NH₂, —NHalkyl, or —N(alkyl)₂.
 5. Acompound according to claim 1, or a pharmaceutically-acceptable salt orhydrate, thereof, having the formula:

in which K is phenyl or thiazolyl; R₃₀ is selected from C₁₋₄alkyl,hydroxy, alkoxy, halogen, nitro, cyano, amino, alkylamino, phenyl, and—C(═O)phenyl; t is 0, 1 or 2; and y is 0, 1 or
 2. 6. A compoundaccording to claim 1, or a pharmaceutically-acceptable salt or hydrate,thereof, in which W is OH, —NR₂₁R₂₂, —NHC(═O)R₂₄, or —NHCO₂alkyl; R₂₁and R₂₂ are independently selected from hydrogen, C₁₋₈alkyl, and(CH₂)_(q)-J, wherein J is selected from napthyl, furanyl, indolyl,imidazolyl, pyrimidinyl, benzothienyl, pyridinyl, pyrrolyl,pyrrolidinyl, thienyl, and C₃₋₇cycloalkyl, wherein the alkyl, alkylene,and/or J groups of R₂₁ and/or R₂₂ are optionally substituted with up tothree R₃₃; R₂₄ is selected from C₁₋₆alkyl, trifluoromethyl, alkoxyalkyl,furylalkyl, alkylaminoethyl, phenyl, pyrollylalkyl, piperidinyl, andpiperidinylalkyl, wherein R₂₄ in turn is optionally substituted with oneto two C₁₋₄alkyl and/or —CO₂(C₁₋₄alkyl); R₃₃ is selected from C₁₋₆alkyl,hydroxy, C₁₋₄alkoxy, amino, C₁₋₄alkylamino, amino C₁₋₄alkyl,trifluoromethyl, halogen, phenyl, benzyl, phenyloxy, benzyloxy,—C(═O)(CH₂)NH₂, —CO₂(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), tetrazolyl,piperidinyl, pyridinyl, and indolyl, wherein when R₃₃ includes a ring,said ring in turn is optionally substituted with one to two C₁₋₄alkyl,hydroxy, methoxy, and/or halogen; and q is 1, 1, 2 or
 3. 7. A compoundaccording to claim 1, or a pharmaceutically-acceptable salt or hydrate,thereof, in which W is a ring selected from:

R₃₄ at each occurrence is attached to any available carbon or nitrogenatom of W and is selected from C₁₋₆alkyl, halogen, amino, aminoalkyl,alkylamino, hydroxy, C₁₋₄alkoxy, hydroxy C₁₋₄alkyl, —C(═O)alkyl,—C(═O)aminoalkyl, —C(═O)phenyl, —C(═O)benzyl, —CO₂alkyl, —CO₂phenyl,—CO₂benzyl, —SO₂alkyl, —SO₂aminoalkyl, —SO₂phenyl, —SO₂benzyl, phenyl,benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl,pyridinyl, pyrimidinyl, and tetrazolyl, and/or two R₃₄ when attached totwo adjacent carbon atoms or adjacent carbon and nitrogen atoms may betaken together to form a fused benzo, heterocyclo, or heteroaryl ring,and/or two R₃₄ when attached to the same carbon atom (in the case of anon-aromatic ring) may form keto (═O), and each R₃₄ in turn isoptionally substituted with up to two R₃₅; R₃₅ is selected from halogen,trifluoromethyl, C₁₋₄alkyl, cyano, nitro, trifluoromethoxy, amino,alkylamino, aminoalkyl, hydroxy, and C₁₋₄alkoxy; w is selected from 0,1, or 2; u is selected from 0, 1, 2, and 3; and v is 0, 1 or
 2. 8. Acompound according to claim 1, or a pharmaceutically-acceptable salt orhydrate, thereof, in which R₈ and R₉ are selected independently fromhydrogen, alkyl, —(CH₂)_(j)—C(═O)alkyl, —(CH₂)_(j)-phenyl,—(CH₂)_(j)-napthyl, —(CH₂)_(j)—C₄₋₇cycloalkyl, —(CH₂)_(j)-heterocyclo,and —(CH₂)_(j)— heteroaryl, provided R₈ and R₉ are not both hydrogen, orR₈ and R₉ together form a spirocycloalkyl or spiroheterocyclic ring; andj is selected from 0, 1, 2 and
 3. 9. A compound according to claim 1, ora pharmaceutically-acceptable salt or hydrate, thereof, in which


10. A compound according to claim 1, or a pharmaceutically-acceptablesalt or hydrate, thereof, in which R₂ is selected from, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkenylene-K, and —CH₂)_(g)—K; K is selected fromphenyl, napthyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, andC₅₋₆cycloalkyl, wherein each group K in turn is optionally substitutedwith one to three R₃₀ or has a benzene ring fused thereto, which alsomay be substituted with one to three R₃₀; R₃₀ is selected fromC₁₋₄alkyl, hydroxy, alkoxy, halogen, nitro, cyano, amino, alkylamino,phenyl, and acylphenyl; and g is 0, 1, 2 or
 3. 11. A compound accordingto claim 1, or a pharmaceutically-acceptable salt or hydrate, thereof,in which -X(R₁)—CH(R₂)—CH(R₃)_(r)—(CH₂)_(s)—, taken together areselected from C₁₋₄alkylene,


12. A compound according to claim 1, or a pharmaceutically-acceptablesalt or hydrate, thereof, in which R₁ is hydrogen or C₁₋₄alkyl.
 13. Acompound according to claim 1, or a pharmaceutically-acceptable salthydrate, or prodrug thereof, in which G is C₂₋₄alkenyl, NHC(═O)R₁₉,SO₂R₁₇, or when y is 0, G may also be pyrrolidinyl, piperidinyl,pyrrolidinyl(lower alkyl), or piperidinyl(lower alkyl); W is —NR₂₁R₂₂,NR₂₁C(═O)R₂₄, azetidinyl, or imidazolyl; R₁₇ and R₁₉ are lower alkyl,and when W is imidazolyl, R₁₉ may be joined with W to form aheterocycle; R₂₁ and R₂₂ are selected from hydrogen and lower alkyl; andy is 0, 1, or
 2. 14. A compound having the formula,

or a pharmaceutically-acceptable salt or hydrate, thereof, in which: R₁is hydrogen or C₁₋₆alkyl or is taken together with R₂ or R₃ to form amonocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle; R₂is C₁₋₆alkyl or C₂₋₆alkenyl optionally substituted with one to aryl,cycloalkyl, or heteroaryl, provided that where G is C₂₋₆ alkenyl,A₁—NR₁₈CO₂R₁₉, or A₁—SO₂R₁₇, or when y is 0, R₂ may be or C₁₋₆alkyl orC₂₋₆alkenyl, each optionally substituted with heteroaryl;

G is selected from: a) —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, and—SO₂R₁₇, b) C₁₋₆alkylene or C₂₋₆alkenylene joined to one of cyano,—OR₁₇, —C(═O)R₁₈, —CO₂R₁₈, —C(═O)NR₁₈R₁₉, —NR₁₈C(═O)R₁₉, —NR₁₈CO₂R₁₉,—NR₁₈SO₂R₁₇, —SO₂R₁₇, —NR₂₀C(═O)NR₁₈R₁₉, and —SR₁₈; c)or when W is agroup other than NHR₂₂, G also may be selected from optionallysubstituted pyrrolidinyl or piperidinyl; W is selected from —NR₂₁R₂₂,—OR₂₃, —NR₂₁C(═O)R₂₄, —NR₂₁CO₂R₂₄, amidino, guanidino, or a substitutedor unsubstituted heterocyclo, heteroaryl, or cycloalkyl group selectedfrom azetidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyridyl,pyrazinyl, pyridazinyl, 1,2-dihydropyridazinyl, pyranyl,tetrahydropyranyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolidinyl,piperidinyl, thiazolyl, tetrahydrothiazolyl, thienyl, furyl,tetrahydrofuryl, morpholinyl, isoquinolinyl, tetrahydroisoquinolinyl,tetrazolyl, oxazolyl, tetrahydro-oxazolyl, and C₃₋₇cycloalkyl, whereinsaid heteroaryl, heterocyclo or cycloalkyl groups may additionally havefused thereto an optionally substituted five-to-seven memberedheterocyclic, heteroaryl, or carbocyclic ring; R₄ and R₇ areindependently selected from hydrogen, alkyl, substituted alkyl, halogen,hydroxy, alkoxy, and keto; R₅, R_(5a), R_(5b), R₆, R_(6a), R_(6b), R₈and R₉ are independently hydrogen, halogen, cyano, alkyl, substitutedalkyl, alkenyl, hydroxy, alkoxy, alkoxycarbonyl, acyl, cycycloalkyl,heterocyclo, aryl, or heteroaryl; or R₅a and R_(5b), R_(6a) and R_(6b),or R₈ and R₉ taken together form a keto group (═O) or a monocyclic orbicyclic cycloalkyl or heterocyclo joined in a spiro fashion to ring E,or alternatively, R₅a and/or R₅b together with R₈ and/or R₉, or R₆aand/or R_(6b) together with R₈ and/or R₉, join together to form a fusedbenzene or heterocyclo ring; provided that, when G is a C₁₋₆alkylsubstituted with —OR₁₇, —CO₂R₁₈, or —C(═O)NR₁₈R₁₉, then R_(5a), R_(5b),R_(6a), and R_(6b) are hydrogen; R₁₀ is selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl, and hetereocyclo; R₁₁is hydrogen or C₁₋₈alkyl; R₁₂ is C₁₋₈alkyl, substituted C₁₋₈alkyl, orcycloalkyl; R₁₇ is alkyl, substituted alkyl, cycloalkyl, aryl,heterocyclo, or heteroaryl; R₁₈, R₁₉, and R₂₀ are independently selectedfrom hydrogen, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl,heterocyclo, C(═O)R₂₈ or a C₁₋₄alkyl or C₂₋₄alkenyl substituted with oneor more of aryl, heteroaryl, cycloalkyl, heterocyclo, alkoxycarbonyl,phenyloxy, and/or benzyloxy, and each of said ringed groups of R₁₈, R₁₉,and R₂₀ in turn is optionally substituted with one to two R₃₆; R₂₁ andR₂₂ are selected from alkyl and substituted alkyl; R₂₃ and R₂₄ areindependently selected from hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, heterocyclo, and cycloalkyl; R₂₈ is hydrogen, alkyl, orsubstituted alkyl; R₃₆ is halogen, methoxy, nitro, phenyl, phenyloxy, oralkylamino; n is 0, 1, 2, 3 or 4; x is 0, 1, or 2; y is 0, 1, 2, 3 or 4;and z is 0, 1, or
 2. 15. A compound according to claim 14, or apharmaceutically-acceptable salt hydrate, or prodrug thereof, having theformula:

wherein G is C₂₋₄alkenyl, NHC(═O)R₁₉, SO₂R₁₇, or when y is 0, G may alsobe pyrrolidinyl, piperidinyl, pyrrolidinyl(lower alkyl), orpipridinyl(lower alkyl); W is OH, —NH₂, NH(lower alkyl), N(loweralkyl)₂, azetidinyl, or imidazolyl, wherein the azetidinyl andimidazolyl are optionally substituted with lower alkyl; R₁₇ and R₁₉ arelower alkyl or phenyl; R₃₀ is C₁₋₄alkyl, hydroxy, methoxyl, ethoxy,halogen, nitro, cyano, amino, C₁₋₄alkylamino, phenyl, or C(═O)phenyl;and y is 0, 1, or
 2. 16. A compound according to claim 15, or apharmaceutically-acceptable salt or hydrate, thereof, in which E is


17. A compound according to claim 14, or a pharmaceutically-acceptablesalt or hydrate, thereof, in which G is NHC(═O)(alkyl) or NHC(═O)phenyl.18. A compound according to claim 1, having the formula,

or a pharmaceutically-acceptable salt or hydrate, thereof.
 19. Apharmaceutical composition comprising at least one compound according toclaim 1 or a pharmaceutically-acceptable salt or hydrate, thereof; and apharmaceutically-acceptable carrier or diluent.
 20. A pharmaceuticalcomposition comprising (i) at least one compound according to claim 1 ora pharmaceutically-acceptable salt hydrate, or prodrug thereof; (ii) atleast one second compound effective for treating an inflammatory orimmune disease, a cardiovascular disease, or a neurodegenerativecondition; and (iii) a pharmaceutically-acceptable carrier or diluent.21. The pharmaceutical composition according to claim 20 in which the atleast one second compound comprises a phosphodiesterase inhibitor.
 22. Amethod of treating a melanocortin-receptor associated condition, themethod comprising administering to a warm-blooded species in need ofsuch treatment a therapeutically-effective amount of at least onecompound according to claim
 1. 23. The method of claim 22 in which themelanocortin-receptor associated condition is an MC-1R or MC-4Rcondition.